Heteroaryl benzamide derivatives for use as glk activators in the treatment of diabetes

ABSTRACT

Compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , HET-1 and HET-2 are as described in the specification, and their salts and pro-drugs, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. Processes for preparing compounds of formula (I) are also described.

The present invention relates to a group of benzoyl amino heterocyclylcompounds which are useful in the treatment or prevention of a diseaseor medical condition mediated through glucokinase (GLK or GK), leadingto a decreased glucose threshold for insulin secretion. In addition thecompounds are predicted to lower blood glucose by increasing hepaticglucose uptake. Such compounds may have utility in the treatment of Type2 diabetes and obesity. The invention also relates to pharmaceuticalcompositions comprising said compounds and to methods of treatment ofdiseases mediated by GLK using said compounds.

In the pancreatic β-cell and liver parenchymal cells the main plasmamembrane glucose transporter is GLUT2. Under physiological glucoseconcentrations the rate at which GLUT2 transports glucose across themembrane is not rate limiting to the overall rate of glucose uptake inthese cells. The rate of glucose uptake is limited by the rate ofphosphorylation of glucose to glucose-6-phosphate (G-6-P) which iscatalysed by glucokinase (GLK) [1]. GLK has a high (6-10 mM) Km forglucose and is not inhibited by physiological concentrations of G-6-P[1]. GLK expression is limited to a few tissues and cell types, mostnotably pancreatic β-cells and liver cells (hepatocytes) [1]. In thesecells GLK activity is rate limiting for glucose utilisation andtherefore regulates the extent of glucose induced insulin secretion andhepatic glycogen synthesis. These processes are critical in themaintenance of whole body glucose homeostasis and both are dysfunctionalin diabetes [2].

In one sub-type of diabetes, Maturity-Onset Diabetes of the Young Type 2(MODY-2), the diabetes is caused by GLK loss of function mutations[3,4]. Hyperglycaemia in MODY-2 patients results from defective glucoseutilisation in both the pancreas and liver [5]. Defective glucoseutilisation in the pancreas of MODY-2 patients results in a raisedthreshold for glucose stimulated insulin secretion. Conversely, rareactivating mutations of GLK reduce this threshold resulting in familialhyperinsulinism [6, 6a, 7]. In addition to the reduced GLK activityobserved in MODY-2 diabetics, hepatic glucokinase activity is alsodecreased in type 2 diabetics [8]. Importantly, global or liverselective overexpression of GLK prevents or reverses the development ofthe diabetic phenotype in both dietary and genetic models of the disease[9-12]. Moreover, acute treatment of type 2 diabetics with fructoseimproves glucose tolerance through stimulation of hepatic glucoseutilisation [13]. This effect is believed to be mediated through afructose induced increase in cytosolic GLK activity in the hepatocyte bythe mechanism described below [13].

Hepatic GLK activity is inhibited through association with GLKregulatory protein (GLKRP). The GLK/GLKRP complex is stabilised byfructose-6-phosphate (F6P) binding to the GLKRP and destabilised bydisplacement of this sugar phosphate by fructose-1-phosphate (F1P). F1Pis generated by fructokinase mediated phosphorylation of dietaryfructose. Consequently, GLK/GLKRP complex integrity and hepatic GLKactivity is regulated in a nutritionally dependent manner as F6P isdominant in the post-absorptive state whereas F1P predominates in thepost-prandial state. In contrast to the hepatocyte, the pancreaticβ-cell expresses GLK in the absence of GLKRP. Therefore, β-cell GLKactivity is regulated extensively by the availability of its substrate,glucose. Small molecules may activate GLK either directly or throughdestabilising the GLK/GLKRP complex. The former class of compounds arepredicted to stimulate glucose utilisation in both the liver and thepancreas whereas the latter are predicted to act selectively in theliver. However, compounds with either profile are predicted to be oftherapeutic benefit in treating Type 2 diabetes as this disease ischaracterised by defective glucose utilisation in both tissues.

GLK, GLKRP and the K_(ATP) channel are expressed in neurones of thehypothalamus, a region of the brain that is important in the regulationof energy balance and the control of food intake [14-18]. These neuroneshave been shown to express orectic and anorectic neuropeptides [15, 19,20] and have been assumed to be the glucose-sensing neurones within thehypothalamus that are either inhibited or excited by changes in ambientglucose concentrations [17, 19, 21, 22]. The ability of these neuronesto sense changes in glucose levels is defective in a variety of geneticand experimentally induced models of obesity [23-28].Intracerebroventricular (icv) infusion of glucose analogues, that arecompetitive inhibitors of glucokinase, stimulate food intake in leanrats [29,30]. In contrast, icv infusion of glucose suppresses feeding[31]. Thus, small molecule activators of GLK may decrease food intakeand weight gain through central effects on GLK. Therefore, GLKactivators may be of therapeutic use in treating eating disorders,including obesity, in addition to diabetes. The hypothalamic effectswill be additive or synergistic to the effects of the same compoundsacting in the liver and/or pancreas in normalising glucose homeostasis,for the treatment of Type 2 diabetes. Thus the GLK/GLKRP system can bedescribed as a potential “Diabesity” target (of benefit in both Diabetesand Obesity).

GLK is also expressed in specific entero-endocrine cells where it isbelieved to control the glucose sensitive secretion of the incretinpeptides GIP (glucose-dependent insulinotropic polypeptide) and GLP-1(Glucagon-Like Peptide-1) from gut K-cells and L-cells respectively (32,33, 34). Therefore, small molecule activators of GLK may have additionalbeneficial effects on insulin secretion, b-cell function and survivaland body weight as a consequence of stimulating GIP and GLP-1 secretionfrom these entero-endocrine cells.

In WO00/58293 and WO01/44216 (Roche), a series of benzylcarbamoylcompounds are described as glucokinase activators. The mechanism bywhich such compounds activate GLK is assessed by measuring the directeffect of such compounds in an assay in which GLK activity is linked toNADH production, which in turn is measured optically—see details of thein vitro assay described hereinafter. Compounds of the present inventionmay activate GLK directly or may activate GLK by inhibiting theinteraction of GLKRP with GLK.

Further GLK activators have been described in WO03/095438 (substitutedphenylacetamides, Roche), WO03/055482 (carboxamide and sulphonamidederivatives, Novo Nordisk), WO2004/002481 (arylcarbonyl derivatives,Novo Nordisk), and in WO03/080585 (amino-substitutedbenzoylaminoheterocycles, Banyu).

Our International application Number: WO03/000267 describes a group ofbenzoyl amino pyridyl carboxylic acids which are activators of theenzyme glucokinase (GLK).

Our International application Number: WO03/015774 describes compounds ofthe Formula (A):

wherein R³ is a substituted heterocycle other than a carboxylic acidsubstituted pyridyl.

International application WO2004/076420 (Banyu) describes compoundswhich are generally a subset of those described in WO03/015774, whereinfor example R¹ is an (substituted) alkyl ether and R² is (substituted)phenoxy.

We have surprisingly found a small group of compounds, generally aselected subgroup of those described in WO 03/015774, which havegenerally superior potency for the GLK enzyme, and more advantageousphysical properties, including, for example, higher aqueous solubility,higher permeability, and/or lower plasma protein binding. Consequently,such compounds having a balance of these properties would be expected todisplay higher plasma free drug levels and superior in vivo efficacyafter oral dosing as determined, for example, by activity in OralGlucose Tolerance Tests (OGTTs). Therefore this group of compounds wouldbe expected to provide superior oral exposure at a lower dose andthereby be particularly suitable for use in the treatment or preventionof a disease or medical condition mediated through GLK. The compounds ofthe invention may also have superior potency and/or advantageousphysical properties (as described above) and/or favourable toxicityprofiles and/or favourable metabolic profiles in comparison with otherGLK activators known in the art, as well as those described in WO03/015774.

Thus, according to the first aspect of the invention there is provided acompound of Formula (I):

wherein:R¹ is selected from isopropyl, but-2-yl, cyclopentyl,1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-hydroxybut-2-yl,tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl,1-methoxybut-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl,2-hydroxybut-1-yl, 2-methoxybut-1-yl, 1-fluoromethoxyprop-2-yl,1,1-difluoromethoxyprop-2-yl and 1-trifluoromethoxyprop-2-yl;HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing anitrogen atom in the 2-position and optionally 1 or 2 further ringheteroatoms independently selected from O, N and S; which ring isoptionally substituted on any nitrogen atom (provided it is not therebyquaternised) by a substituent selected from R⁷ and/or on 1 or 2available carbon atoms by a substituent independently selected from R⁶;HET-2 is a 5- or 6-membered heteroaryl ring, containing 1, 2 or 3 ringhetereoatoms independently selected from O, S and N; which ring issubstituted on an available carbon atom by a substituent selected fromR², and is optionally further substituted on 1 or 2 available carbonatoms by a substituent independently selected from R³ and/or on anavailable nitrogen atom (provided it is not thereby quaternised) by asubstituent selected from R¹⁰;R² is selected from —C(O)NR⁴R⁵ and —SO₂NR⁴R⁵;R³ is selected from methyl, trifluoromethyl and halo;R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a 4 to 7 membered saturated or partially unsaturated heterocyclylring, optionally containing 1 or 2 further heteroatoms (in addition tothe linking N atom) independently selected from O, N and S, wherein a—CH₂— group can optionally be replaced by a —C(O)— and wherein a sulphuratom in the ring may optionally be oxidised to a S(O) or S(O)₂ group;which ring is optionally substituted on an available carbon atom by 1 or2 substituents independently selected from R⁸ and/or on an availablenitrogen atom by a substituent selected from R⁹; or R⁴ and R⁵ togetherwith the nitrogen atom to which they are attached form a 6-10 memberedbicyclic saturated or partially unsaturated heterocyclyl ring,optionally containing 1 further nitrogen atom (in addition to thelinking N atom), wherein a —CH₂— group can optionally be replaced by a—C(O)—; which ring is optionally substituted on an available carbon by 1substituent selected from hydroxy and R³ or on an available nitrogenatom by methyl;R⁶ is independently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,(1-4C)alkylamino(1-4C)alkyl and di(1-4C)alkylamino(1-4C)alkyl;R⁷ is independently selected from (1-4C)alkyl, halo(1-4C)alkyl,dihalo(1-4C)alkyl, trihalo(1-4C)alkyl, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,(1-4C)alkylamino(1-4C)alkyl and di(1-4C)alkylamino(1-4C)alkyl;R⁸ is selected from hydroxy, (1-4C)alkoxy, (1-4C)alkyl, aminocarbonyl,(1-4C)alkylaminocarbonyl, di(1-4C)alkylaminocarbonyl, (1-4C)alkylamino,di(1-4C)alkylamino, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl and—S(O)p(1-4C)alkyl;R⁹ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl, aminocarbonyl,(1-4C)alkylaminocarbonyl, di(1-4C)alkylaminocarbonyl,(1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl and —S(O)p(1-4C)alkyl;R¹⁰ is selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, —C(O)(1-4C)alkyl, benzyl, and(1-4C)alkylsulfonyl;p is (independently at each occurrence) 0, 1 or 2;or a salt thereof.

In another aspect of the invention there is provided a compound offormula (I) as hereinbefore defined wherein R¹ is selected fromisopropyl, but-2-yl, 1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl,but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-hydroxybut-2-yl,tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl,1-methoxybut-2-yl, 1-fluoromethoxyprop-2-yl,1,1-difluoromethoxyprop-2-yl and 1-trifluoromethoxyprop-2-yl;

or a salt thereof.

In another aspect of the invention there is provided a compound offormula (I) as hereinbefore defined wherein R¹ is selected fromisopropyl, but-2-yl, 1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl,but-1-yn-3-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-hydroxybut-2-yl,tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl,1-methoxybut-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl,2-hydroxybut-1-yl, 2-methoxybut-1-yl, 1-fluoromethoxyprop-2-yl,1,1-difluoromethoxyprop-2-yl and 1-trifluoromethoxyprop-2-yl; or a saltthereof.

In another aspect of the invention there is provided a compound offormula (I) as hereinbefore defined wherein R³ is halo; or a saltthereof.

In another aspect of the invention there is provided a compound offormula (I) as hereinbefore defined wherein R⁷ is independently selectedfrom (1-4C)alkyl, hydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl,(1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,(1-4C)alkylamino(1-4C)alkyl and di(1-4C)alkylamino(1-4C)alkyl; or a saltthereof.

It will be appreciated that, where definitions of heterocylyl groupsHET-1 and HET-2 encompass heteroaryl rings which may be substituted onnitrogen, such substitution may not result in charged quaternarynitrogen atoms, removal of aromaticity of the ring or unstablestructures. It will be appreciated that the definitions of HET-1 andHET-2 are not intended to include any O—O, O—S or S—S bonds. It will beappreciated that the definitions of HET-1 and HET-2 are not intended toinclude unstable structures.

It will be understood that any single carbon atom in HET-1 may only besubstituted by one group R⁶ in order to maintain aromaticity of thering. Up to two different carbon atoms in a HET-1 ring may besubstituted by an R⁶ group, each of which may be the same or different,provided the structure thereby formed is stable and aromatic.

It will be understood that any single carbon atom in HET-2 may only besubstituted by one group R³ in order to maintain aromaticity of thering. Up to two different carbon atoms in a HET-2 ring may besubstituted by an R³ group, each of which may be the same or different,provided the structure thereby formed is stable and aromatic.

It will be understood that R⁸ can be present on any or all availablecarbon atoms in the heterocyclic ring formed by NR⁴R⁵; each carbon atomcan be substituted with 1 or 2 R⁸ groups which may be the same ordifferent, provided the structure thereby formed is stable (so, forexample, it is not intended to cover gem-dihydroxy substitution).

It will be understood that where a compound of the formula (I) containsmore than one group R⁵, they may be the same or different.

It will be understood that where a compound of the formula (I) containsmore than one group R³, they may be the same or different.

A similar convention applies for all other groups and substituents on acompound of formula (I) as hereinbefore defined.

Compounds of Formula (I) may form salts which are within the ambit ofthe invention. Pharmaceutically acceptable salts are preferred althoughother salts may be useful in, for example, isolating or purifyingcompounds.

In another aspect, the invention relates to compounds of formula (I) ashereinabove defined or to a pharmaceutically acceptable salt.

In this specification the generic term “alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for the straightchain version only and references to individual branched-chain alkylgroups such as t-butyl are specific for the branched chain version only.For example, “(1-4C)alkyl” includes methyl, ethyl, propyl, isopropyl andt-butyl. An analogous convention applies to other generic terms.

For the avoidance of doubt, reference to the group HET-1 containing anitrogen in the 2-position, is intended to refer to the 2-positionrelative to the amide nitrogen atom to which the group is attached. Forexample, HET-1 encompasses but is not limited to the followingstructures:

Suitable examples of HET-1 as a 5- or 6-membered, C-linked heteroarylring as hereinbefore defined, include thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl,pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl.

Suitable examples of HET-2 include thienyl, furyl, thiazolyl,isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl,imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl andtriazolyl. Further suitable examples of HET-2 include aromaticheterocycles where a ring nitrogen or sulfur atom has been oxidised butaromaticity has been preserved, for example a pyridine N-oxide. Furthersuitable examples of HET-2 include thiazolyl, pyridyl, pyrazinyl,pyridazinyl and pyrimidinyl.

Suitable examples for a 4-7 membered ring formed by R⁴ and R⁵ togetherwith the nitrogen to which they are attached, as hereinbefore defined,include morpholino, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl,homopiperazinyl, homo-morpholino, homo-thiomorpholino (and versionsthereof wherein the sulfur is oxidised to an SO or S(O)₂ group) andhomo-piperidinyl. A further suitable example is thiomorpholino (andversions thereof wherein the sulfur is oxidised to an SO or S(O)₂group).

Suitable examples for a 6-10 membered bicyclic heterocyclic ring formedby R⁴ and R⁵ together with the nitrogen to which they are attached, ashereinbefore defined, are bicyclic saturated or partially unsaturatedheterocyclyl ring such as those illustrated by the structures shownbelow (wherein the dotted line indicates the point of attachment to therest of the molecule and wherein R represents the optional substituentsfor carbon or nitrogen defined hereinbefore):

In particular such a ring system is a [2,2,1] system such as

(7-azabicyclo[2.2.1]hept-7-yl).

In another embodiment, such a ring system is a [2.1.1] system such as

(2-azabicyclo[2.1.1]hex-2-yl).

Examples of (1-4C)alkyl include methyl, ethyl, propyl, isopropyl, butyland tert-butyl; examples of (3-6C)cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl; examples of halo include fluoro,chloro, bromo and iodo; examples of halo(1-4C)alkyl includefluoromethyl, chloromethyl, fluoroethyl, chloroethyl, fluoropropyl andfluorobutyl; examples of dihalo(1-4C)alkyl include difluoromethyl,1,1-difluoroeth-2-yl, 1,2-difluoroeth-2-yl, 1,1-dichloroeth-2-yl,1,2-dichloroeth-2-yl, and 1,1-difluoroprop-3-yl; examples oftrihalo(1-4C)alkyl include trifluoromethyl and 1,1,1-trifluoroeth-2-yl;examples of hydroxy(1-4C)alkyl include hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl and4-hydroxybutyl; examples of (1-4C)alkoxy(1-4C)alkyl includemethoxymethyl, ethoxymethyl, tert-butoxymethyl, 2-methoxyethyl,2-ethoxyethyl, methoxypropyl, 2-methoxypropyl and methoxybutyl; exampleof (1-4C)alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy andtert-butoxy; examples of (1-4C)alkylS(O)p(1-4C)alkyl (where p is 0, 1 or2) include methylsulfinylmethyl, ethylsulfinylmethyl,ethylsulfinylethyl, methylsulfinylpropyl, methylsulfinylbutyl,methylsulfonylmethyl, ethylsulfonylmethyl, ethylsulfonylethyl,methylsulfonylpropyl, methylsulfonylbutyl, methylthiomethyl,ethylthiomethyl, ethylthioethyl, methylthiopropyl, and methylthiobutyl;examples of (1-4C)alkylsulfonyl include methylsulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl and tert-butylsulfonyl; examples of—S(O)p(1-4C)alkyl include (1-4C)alkylsulfonyl, methylsulfinyl,ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, tert-butylsulfinyl,methylthio, ethylthio, propylthio, isopropylthio and tert-butylthio;examples of amino(1-4C)alkyl include aminomethyl, aminoethyl,2-aminopropyl, 3-aminopropyl, 1-aminoisopropyl and 4-aminobutyl;examples of (1-4C)alkylamino(1-4C)alkyl include (N-methyl)aminomethyl,(N-ethyl)aminomethyl, 1-((N-methyl)amino)ethyl,2-((N-methyl)amino)ethyl, (N-ethyl)aminoethyl, (N-methyl)aminopropyl,and 4-((N-methyl)amino)butyl; examples of di(1-4C)alkylamino(1-4C)alkylinclude dimethylaminomethyl, methyl(ethyl)aminomethyl,methyl(ethyl)aminoethyl, (N,N-diethyl)aminoethyl,(N,N-dimethyl)aminopropyl and (N,N-dimethyl)aminobutyl; examples of—C(O)(1-4C)alkyl and (1-4C)alkylcarbonyl include methylcarbonyl,ethylcarbonyl, propylcarbonyl and tert-butyl carbonyl; examples of(1-4C)alkylamino include methylamino, ethylamino, propylamino,isopropylamino, butylamino and tert-butylamino; examples ofdi(1-4C)alkylamino include dimethylamino, diethylamino,N-methyl-N-ethylamino, dipropylamino, N-isopropyl-N-methylamino anddibutylamino; examples of (1-4C)alkylaminocarbonyl includemethylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl,isopropylaminocarbonyl, butylaminocarbonyl and tert-butylaminocarbonyl;examples of di(1-4C)alkylaminocarbonyl include dimethylaminocarbonyl,diethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl,dipropylaminocarbonyl, N-isopropyl-N-methyaminocarbonyl anddibutylaminocarbonyl.

It is to be understood that, insofar as certain of the compounds ofFormula (I) defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms, the invention includesin its definition any such optically active or racemic form whichpossesses the property of stimulating GLK directly or inhibiting theGLKIGLKRP interaction. The synthesis of optically active forms may becarried out by standard techniques of organic chemistry well known inthe art, for example by synthesis from optically active startingmaterials or by resolution of a racemic form. It is also to beunderstood that certain compounds may exist in tautomeric forms and thatthe invention also relates to any and all tautomeric forms of thecompounds of the invention which activate GLK.

It is also to be understood that certain compounds of the formula (I)and salts thereof can exist in solvated as well as unsolvated forms suchas, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which activate GLK.

In another aspect, the invention relates to compounds of formula (I) ashereinabove defined or to a pro-drug thereof. Suitable examples ofpro-drugs of compounds of formula (I) are in-vivo hydrolysable esters ofcompounds of formula (I). Therefore in another aspect, the inventionrelates to compounds of formula (I) as hereinabove defined or to anin-vivo hydrolysable ester thereof.

In one embodiment of the invention are provided compounds of formula(I), in an alternative embodiment are providedpharmaceutically-acceptable salts of compounds of formula (I), in afurther alternative embodiment are provided in-vivo hydrolysable estersof compounds of formula (I), and in a further alternative embodiment areprovided pharmaceutically-acceptable salts of in-vivo hydrolysableesters of compounds of formula (I).

The compounds of the invention may be administered in the form of apro-drug. A pro-drug is a bioprecursor or pharmaceutically acceptablecompound being degradable in the body to produce a compound of theinvention (such as an ester or amide of a compound of the invention,particularly an in-vivo hydrolysable ester). Various forms of prodrugsare known in the art. For examples of such prodrug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and    Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et    al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen;-   c) H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”,    by H. Bundgaardp. 113-191 (1991);-   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988); and-   f) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).    The contents of the above cited documents are incorporated herein by    reference.

Examples of pro-drugs are as follows. An in-vivo hydrolysable ester of acompound of the invention containing a carboxy or a hydroxy group is,for example, a pharmaceutically-acceptable ester which is hydrolysed inthe human or animal body to produce the parent acid or alcohol. Suitablepharmaceutically-acceptable esters for carboxy include C₁ toC₆alkoxymethyl esters for example methoxymethyl, C₁ toC₆alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidylesters, C₃ to C₈cycloalkoxycarbonyloxy C₁ to C₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, forexample 5-methyl-1,3-dioxolen-2-onylmethyl; and(1-6C)alkoxycarbonyloxyethyl esters.

An in-vivo hydrolysable ester of a compound of the invention containinga hydroxy group includes inorganic esters such as phosphate esters(including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers andrelated compounds which as a result of the in-vivo hydrolysis of theester breakdown to give the parent hydroxy group/s. Examples ofα-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a benzoxazinone derivative of theinvention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, an ammonium salt or a salt with anorganic base which affords a physiologically-acceptable cation, forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

In a further aspect of the invention there is provided a compound offormula (I) which is a compound of formula (IA), or a salt thereof:

wherein each of X¹, X² and X³ is independently selected from CH, N, Sand O;X⁴ is absent (to make a 5-membered ring) or is selected from CH, N, Oand S;provided that at least one of X¹, X², X³ and X⁴ is CH and provided thatthere are no O—O, O—S or S—S bonds within the ring;R³, if present, is selected from methyl, trifluoromethyl and halo;R¹, R² and HET-1 are as defined for a compound of formula (I).

It will be understood that the dotted circle inside the ring containingX¹ to X⁴ (that is, the HET-2 ring) is intended to indicate that the ringis aromatic, although the precise number and position of the doublebonds will be dependent on the nature of X¹ to X⁴.

References herein to a compound of formula (I) should generally beunderstood to apply equally to a compound of formula (IA), whetherexplicitly stated or not, unless the context indicates otherwise.

Particular examples of compounds of formula (I) and (IA) includecompounds of formulae (IB), (IC) and/or (ID):

wherein R¹, R² and HET-1 are as defined for a compound of formula (I).

Preferred values of each variable group are as follows. Such values maybe used where appropriate with any of the values, definitions, claims,aspects or embodiments defined hereinbefore or hereinafter. Inparticular, each may be used as an individual limitation on the broadestdefinition of formula (I) or (IA). Further, each of the following valuesmay be used in combination with one or more of the other followingvalues to limit the broadest definition of formula (I) or (IA) or tolimit any narrower definitions of formula (I) or (IA) in any of theaspects hereinbefore or hereinafter. Where appropriate each of thefollowing values may also be used to limit any definition withinformulae (IB), (IC) and/or (ID).

(1) R¹ is of sub-formula X:

wherein R^(x) is selected from methyl, ethyl, trifluoromethyl, ethynyl,hydroxymethyl, hydroxyethyl, methoxymethyl, fluoromethoxymethyl,difluoromethoxymethyl and trifluoromethoxymethyl; preferably R^(x) isselected from methyl, ethyl, trifluoromethyl, ethynyl, hydroxymethyl,hydroxyethyl, methoxymethyl, fluoromethoxymethyl anddifluoromethoxymethyl(2) R¹ is of sub-formula Y:

wherein R^(y) is selected from hydroxymethyl and methoxymethyl(3) R¹ is 1-hydroxyprop-2-yl and the configuration is preferably (S),that is R¹—O— is:

(4) R¹ is 1-methoxyprop-2-yl and the configuration is preferably (S),that is R′—O— is:

(5) R¹ is selected from isopropyl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl,1-hydroxyprop-2-yl, hydroxybut-3-yl and 1-methoxyprop-2-yl(6) R¹ is 1,1,1-trifluoroprop-2-yl, 1-fluoromethoxyprop-2-yl,1,1-difluoromethoxyprop-2-yl or 1-trifluoromethoxyprop-2-yl(7) R¹ is 1-fluoromethoxyprop-2-yl, 1,1-difluoromethoxyprop-2-yl or1-trifluoromethoxyprop-2-yl, particularly 1-fluoromethoxyprop-2-yl or1,1-difluoromethoxyprop-2-yl(8) R¹ is 1,1-difluoromethoxyprop-2-yl, particularly with thestereochemistry:

(9) R¹ is tetrahydrofuryl or tetrahydropyranyl(10) R¹ is tetrahydrofuryl in the (S) configuration, that is:

(11) R¹ is tetrahydrofuryl in the (R) configuration, that is:

(12) R¹ is 4-tetrahydropyranyl:

(13) R¹ is 2-hydroxy-but-3-yl and the configuration is preferably suchthat R′—O— is:

(14) R¹ is 1-hydroxybut-2-yl or 1-methoxybut-2-yl(15) R¹ is selected from isopropyl, but-2-yl, 1,1,1-trifluoroprop-2-yl,1,3-difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl,2-hydroxybut-3-yl, tetrahydrofuryl, tetrahydropyranyl,1-methoxyprop-2-yl, 1-fluoromethoxyprop-2-yl,1,1-difluoromethoxyprop-2-yl and 1-trifluoromethoxyprop-2-yl(16) R¹ is selected from 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl,2-hydroxybut-1-yl and 2-methoxybut-1-yl(17) R¹ is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1,1-difluoromethoxyprop-2-yl,tetrahydrofuryl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl(18) R¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl(19) R¹ is selected from tetrahydrofuryl, 1-difluoromethoxyprop-2-yl,1,3-difluoroprop-2-yl, and 2-hydroxybut-3-yl(20) R¹ is selected from isopropyl, tetrahydrofuryl, 1-hydroxyprop-2-yland 1-methoxyprop-2-yl(21) R¹ is selected from 1-hydroxyprop-2-yl and 1-methoxyprop-2-yl, forexample (2S)-1-hydroxyprop-2-yl and (2S)-1-methoxyprop-2-yl(22) R¹ is selected from isopropyl, but-2-yl, cyclopentyl,1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-hydroxybut-2-yl,tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl,1-methoxybut-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl,2-hydroxybut-1-yl, 2-methoxybut-1-yl, 1-fluoromethoxyprop-2-yl and1,1-difluoromethoxyprop-2-yl(23) R¹ is selected from isopropyl, but-2-yl, cyclopentyl,1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-hydroxybut-2-yl,tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl,1-methoxybut-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl,2-hydroxybut-1-yl, 2-methoxybut-1-yl and 1,1-difluoromethoxyprop-2-yl(24) HET-1 is a 5-membered heteroaryl ring(25) HET-1 is a 6-membered heteroaryl ring(26) HET-1 is substituted with 1 or 2 substituents independentlyselected from R⁶(27) HET-1 is substituted with 1 substituent selected from R⁶(28) HET-1 is substituted with 1 substituent selected from R⁷(29) HET-1 is unsubstituted(30) HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl,pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl,oxazolyl, isoxazolyl, oxadiazolyl, and triazolyl(31) HET-1 is selected from thiazolyl, isothiazolyl, thiadiazolyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl(32) HET-1 is selected from pyridyl, pyrazinyl, pyridazinyl andpyrimidinyl(33) HET-1 is selected from thiazolyl, pyrazolyl and oxazolyl(34) HET-1 is selected from thiadiazolyl and oxadiazolyl(35) HET-1 is selected from 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl(36) HET-1 is selected from 1,2,4-oxadiazolyl and 1,2,4-oxadiazolyl(37) HET-1 is pyrazolyl, particularly N-methylpyrazolyl(38) HET-1 is pyrazinyl(39) HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl andpyrazinyl(40) HET-1 is selected from thiazolyl, pyrazolyl, and thiadiazolyl,optionally substituted with (1-4C)alkyl(41) HET-1 is pyrazolyl, particularly N-methylpyrazolyl(42) HET-1 is pyrazolyl (optionally substituted with ethyl, isopropyl or1 or 2 methyl), thiazolyl (optionally substituted with methyl),pyrazinyl (optionally substituted with methyl), pyridyl (optionallysubstituted by fluoro), isoxazolyl (optionally substituted with methyl)and thiadiazolyl (optionally substituted with methyl)(43) HET-1 is pyrazolyl (optionally substituted with ethyl, isopropyl,difluoromethyl, or 1 or 2 methyl), thiazolyl (optionally substitutedwith methyl), pyrazinyl (optionally substituted with methyl), pyridyl(optionally substituted by fluoro), isoxazolyl (optionally substitutedwith methyl) and thiadiazolyl (optionally substituted with methyl)(44) HET-1 is selected from pyrazinyl (optionally substituted withmethyl), pyrazolyl (optionally substituted on carbon by methyl),methylthiadiazolyl (particularly 1,2,4-thiadiazol-5-yl, moreparticularly 3-methyl-1,2,4-thiadiazol-5-yl), thiazolyl (optionallysubstituted with methyl), pyridyl (optionally substituted by fluoro) andisoxazolyl

(45) HET-1 is N-difluoromethylpyrazolyl

(46) HET-1 is 5-methylpyrazin-2-yl(47) HET-1 is pyrazolyl (optionally substituted with ethyl, isopropyl,difluoromethyl, or 1 or 2 methyl), thiazolyl (optionally substitutedwith methyl), pyrazinyl (optionally substituted with methyl), pyridyl(optionally substituted by fluoro), isoxazolyl (optionally substitutedwith methyl) and thiadiazolyl (optionally substituted with methyl); andR¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl; when HET-1 is pyrazolylunsubstituted on nitrogen (ie NH-pyrazolyl), particularly R¹ is selectedfrom 1-methoxyprop-2-yl, isopropyl, and tetrahydrofuryl(48) HET-1 is pyrazolyl (optionally substituted on carbon with methyl),thiazolyl (optionally substituted with methyl), pyrazinyl (optionallysubstituted with methyl), pyridyl (optionally substituted by fluoro),isoxazolyl and methylthiadiazolyl (particularly3-methyl-1,2,4-thiadiazol-5-yl);R¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl; when HET-1 is pyrazolyl,particularly R¹ is selected from 1-methoxyprop-2-yl, isopropyl, andtetrahydrofuryl(49) HET-1 is methylpyrazinyl and R¹ is selected from 1-hydroxyprop-2-yland 1-methoxyprop-2-yl, for example (2S)-1-hydroxyprop-2-yl and(2S)-1-methoxyprop-2-yl(50) HET-1 is pyrazolyl and R¹ is selected from isopropyl,tetrahydrofuryl and 1-methoxyprop-2-yl, for example(2S)-1-methoxyprop-2-yl(51) R⁶ is selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl anddi(1-4C)alkylamino(1-4C)alkyl(52) R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro,hydroxymethyl, methoxymethyl, aminomethyl, N-methylaminomethyl,dimethylaminomethyl(53) R⁶ is selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,(1-4C)alkylamino(1-4C)alkyl, and di(1-4C)alkylamino(1-4C)alkyl(54) R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro,hydroxymethyl and methoxymethyl(55) R⁶ is selected from methyl, ethyl, chloro and fluoro(56) R⁶ is methyl or fluoro, preferably methyl(57) R⁶ is selected from methyl, ethyl, bromo, chloro, fluoro,aminomethyl, N-methylaminomethyl, dimethylaminomethyl, hydroxymethyl andmethoxymethyl(58) R⁶ is selected from methyl, ethyl, aminomethyl,N-methylaminomethyl, dimethylaminomethyl, hydroxymethyl andmethoxymethyl(59) R⁶ is selected from methyl, ethyl, isopropyl and methoxymethyl(60) when 2 substituents R⁶ are present, both are selected from methyl,ethyl, bromo, chloro and fluoro; preferably both are methyl(61) R⁶ is selected from (1-4C)alkylS(O)p(1-4C)alkyl,(1-4C)alkylamino(1-4C)alkyl and di(1-4C)alkylamino(1-4C)alkyl(62) R⁷ is selected from (1-4C)alkyl, hydroxy(1-4C)alkyl anddi(1-4C)alkylamino(1-4C)alkyl(63) R⁷ is selected from methyl, ethyl, hydroxymethyl, methoxymethyl,aminomethyl, N-methylaminomethyl, dimethylaminomethyl(64) R⁷ is selected from (1-4C)alkyl, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,(1-4C)alkylamino(1-4C)alkyl, and di(1-4C)alkylamino(1-4C)alkyl(65) R⁷ is selected from methyl, ethyl, aminomethyl,N-methylaminomethyl, and dimethylaminomethyl(66) R⁷ is selected from methyl, ethyl, hydroxymethyl and methoxymethyl(67) R⁷ is selected from methyl, isopropyl and ethyl(68) R⁷ is selected from methyl, isopropyl, difluoromethyl and ethyl(69) R⁷ is selected from isopropyl and difluoromethyl, particularlydifluoromethyl(70) R⁷ is selected from methyl and ethyl(71) R⁷ is methyl(72) R⁷ is selected from methyl, ethyl, aminomethyl,N-methylaminomethyl, dimethylaminomethyl, hydroxymethyl andmethoxymethyl(73) R⁷ is selected from methyl, ethyl, isopropyl and methoxymethyl(74) when R⁷ is selected from halo(1-4C)alkyl, dihalo(1-4C)alkyl andtrihalo(1-4C)alkyl, each halo is selected from chloro and fluoro, and isin particular fluoro.(75) when R⁷ is selected from halo(1-4C)alkyl, dihalo(1-4C)alkyl andtrihalo(1-4C)alkyl, R⁷ is particularly selected from fluoromethyl,difluoroethyl, difluoromethyl and trifluoromethyl(76) HET-2 is a 5-membered ring(77) HET-2 is a 6-membered ring(78) HET-2 is selected from thienyl, furyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl,pyrimidinyl, oxazolyl, isoxazolyl and oxadiazolyl(79) HET-2 is selected from thienyl, furyl, thiadiazolyl, pyridyl,pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl andoxadiazolyl(80) HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and thienyl(81) HET-2 is selected from pyridyl, pyrazinyl and thiazolyl(82) HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl andthiazolyl(83) HET-2 is selected from pyridyl and pyrazinyl(84) HET-2 is pyrazinyl(85) HET-2 is substituted with a substituent selected from R³(86) HET-2 has one nitrogen substituent selected from R¹⁰(87) R³ is chloro or fluoro(88) R³ is chloro(89) R³ is fluoro(90) R³ is chloro or methyl(91) R³ is fluoro, chloro or methyl

(92) R² is —C(O)NR⁴R⁵ (93) R² is —SO₂NR⁴R⁵

(94) R⁴ and R⁵ together with the nitrogen atom to which they areattached form a 4 membered ring(95) R⁴ and R⁵ together with the nitrogen atom to which they areattached form a 5 membered ring(96) R⁴ and R⁵ together with the nitrogen atom to which they areattached form a 6 membered ring(97) R⁴ and R⁵ together with the nitrogen atom to which they areattached form a 7 membered ring(98) R⁴ and R⁵ together with the nitrogen atom to which they areattached form a fully saturated ring(99) R⁴ and R⁵ together with the nitrogen atom to which they areattached form a ring selected from morpholino, piperidinyl, piperazinyl,pyrrolidinyl and azetidinyl(100) R⁴ and R⁵ together with the nitrogen atom to which they areattached form a ring selected from pyrrolidinyl, morpholino andazetidinyl(101) R⁴ and R⁵ together with the nitrogen atom to which they areattached form a ring selected from 7-azabicyclo[2.2.1]hept-7-yl,pyrrolidinyl, morpholino and azetidinyl(102) R⁴ and R⁵ together with the nitrogen atom to which they areattached form an azetidinyl ring(103) R⁴ and R⁵ together with the nitrogen atom to which they areattached form an azetidinyl or pyrrolidinyl ring(104) R⁴ and R⁵ together with the nitrogen atom to which they areattached form an unsubstituted ring(105) R⁴ and R⁵ together with the nitrogen atom to which they areattached form an ring mono-substituted either with a substituent R⁸ orwith a substituent R⁹(106) R⁴ and R⁵ together with the nitrogen atom to which they areattached form a 6-10 membered bicyclic saturated or partiallyunsaturated ring(107) R⁸ is selected from hydroxy, (1-4C)alkoxy, (1-4C)alkyl(108) R⁸ is selected from hydroxy, methoxy and methyl(109) R⁹ is selected from (1-4C)alkyl and —C(O)(1-4C)alkyl(110) R² is azetidinylcarbonyl or pyrrolidinylcarbonyl, preferablyazetidinylcarbonyl

(109) R¹⁰ is (1-4C)alkyl (111) R¹⁰ is (3-6C)cycloalkyl

(112) R¹⁰ is hydroxy(1-4C)alkyl or (1-4C)alkoxy(1-4C)alkyl

(113) R¹⁰ is —C(O)(1-4C)alkyl

(114) R¹⁰ is benzyl

(115) R¹⁰ is (1-4C)alkylsulfonyl

(116) R¹⁰ is (1-4C)alkyl or benzyl

According to a further feature of the invention there is provided thefollowing preferred groups of compounds of the invention:

In one aspect of the invention there is provided a compound of formula(I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, but-2-yl, 1,1,1-trifluoroprop-2-yl,1,3-difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl,2-hydroxybut-3-yl, tetrahydrofuryl, tetrahydropyranyl,1-methoxyprop-2-yl, 1-fluoromethoxyprop-2-yl and1,1-difluoromethoxyprop-2-yl; HET-1 is a 5- or 6-membered, C-linkedheteroaryl ring containing a nitrogen atom in the 2-position andoptionally 1 or 2 further ring heteroatoms independently selected fromO, N and S; which ring is optionally substituted on any nitrogen atom(provided it is not thereby quaternised) by a methyl or ethyl groupand/or on 1 or 2 available carbon atoms by a methyl or ethyl group;HET-2 is a 5- or 6-membered heteroaryl ring, containing 1, 2 or 3 ringhetereoatoms independently selected from O, S and N; which ring issubstituted on an available carbon atom by a substituent selected fromR², and is optionally further substituted on 1 or 2 available carbonatoms by a substituent independently selected from R³ and/or on anavailable nitrogen atom (provided it is not thereby quaternised) by asubstituent selected from R¹⁰;R² is selected from —C(O)NR⁴R⁵ and —SO₂NR⁴R⁵;R³ is selected from halo;R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a 4 to 7 membered saturated or partially unsaturated heterocyclylring, optionally containing 1 or 2 further heteroatoms (in addition tothe linking N atom) independently selected from O, N and S, wherein a—CH₂— group can optionally be replaced by a —C(O)— and wherein a sulphuratom in the ring may optionally be oxidised to a S(O) or S(O)₂ group;which ring is optionally substituted on an available carbon atom by 1 or2 substituents independently selected from R⁸ and/or on an availablenitrogen atom by a substituent selected from R⁹;R⁸ is selected from hydroxy, (1-4C)alkoxy and (1-4C)alkyl;R⁹ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl, and—S(O)p(1-4C)alkyl;R¹⁰ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl, benzyl, and(1-4C)alkylsulfonyl;p is (independently at each occurrence) 0, 1 or 2.

In one aspect of the invention there is provided a compound of formula(I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, but-2-yl, 1,1,1-trifluoroprop-2-yl,1,3-difluoroprop-2-yl, but-1-yn-3-yl, 1-hydroxyprop-2-yl,2-hydroxybut-3-yl, tetrahydrofuryl, tetrahydropyranyl,1-methoxyprop-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl,2-hydroxybut-1-yl, 2-methoxybut-1-yl, 1-fluoromethoxyprop-2-yl and1,1-difluoromethoxyprop-2-yl;HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing anitrogen atom in the 2-position and optionally 1 or 2 further ringheteroatoms independently selected from O, N and S; which ring isoptionally substituted on any nitrogen atom (provided it is not therebyquaternised) by a methyl or ethyl group and/or on 1 or 2 availablecarbon atoms by a methyl or ethyl group;HET-2 is a 5- or 6-membered heteroaryl ring, containing 1, 2 or 3 ringhetereoatoms independently selected from O, S and N; which ring issubstituted on an available carbon atom by a substituent selected fromR², and is optionally further substituted on 1 or 2 available carbonatoms by a substituent independently selected from R³ and/or on anavailable nitrogen atom (provided it is not thereby quaternised) by asubstituent selected from R¹⁰;R² is selected from —C(O)NR⁴R⁵ and —SO₂NR⁴R⁵;R³ is selected from halo;R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a 4 to 7 membered saturated or partially unsaturated heterocyclylring, optionally containing 1 or 2 further heteroatoms (in addition tothe linking N atom) independently selected from O, N and S, wherein a—CH₂— group can optionally be replaced by a —C(O)— and wherein a sulphuratom in the ring may optionally be oxidised to a S(O) or S(O)₂ group;which ring is optionally substituted on an available carbon atom by 1 or2 substituents independently selected from R⁸ and/or on an availablenitrogen atom by a substituent selected from R⁹;R⁸ is selected from hydroxy, (1-4C)alkoxy and (1-4C)alkyl;R⁹ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl, and—S(O)p(1-4C)alkyl;R¹⁰ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl, benzyl, and(1-4C)alkylsulfonyl;p is (independently at each occurrence) 0, 1 or 2.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, but-2-yl, cyclopentyl,1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, tetrahydrofuryl,tetrahydropyranyl, 1-methoxyprop-2-yl, 2-hydroxyprop-1-yl,2-methoxyprop-1-yl, 2-hydroxybut-1-yl, 2-methoxybut-1-yl,1-fluoromethoxyprop-2-yl and 1,1-difluoromethoxyprop-2-yl;HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing anitrogen atom in the 2-position and optionally 1 or 2 further ringheteroatoms independently selected from O, N and S; which ring isoptionally substituted on any nitrogen atom (provided it is not therebyquaternised) by a methyl, ethyl or isopropyl group and/or on 1 or 2available carbon atoms by a methyl, ethyl or fluoro group;HET-2 is a 5- or 6-membered heteroaryl ring, containing 1, 2 or 3 ringhetereoatoms independently selected from O, S and N; which ring issubstituted on an available carbon atom by a substituent selected fromR², and is optionally further substituted on 1 or 2 available carbonatoms by a substituent independently selected from R³ and/or on anavailable nitrogen atom (provided it is not thereby quaternised) by asubstituent selected from R¹⁰;R² is selected from —C(O)NR⁴R⁵ and —SO₂NR⁴R⁵;R³ is selected from halo;R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a 4 to 7 membered saturated or partially unsaturated heterocyclylring, optionally containing 1 or 2 further heteroatoms (in addition tothe linking N atom) independently selected from O, N and S, wherein a—CH₂— group can optionally be replaced by a —C(O)— and wherein a sulphuratom in the ring may optionally be oxidised to a S(O) or S(O)₂ group;which ring is optionally substituted on an available carbon atom by 1 or2 substituents independently selected from R⁹ and/or on an availablenitrogen atom by a substituent selected from R⁹;R⁸ is selected from hydroxy, (1-4C)alkoxy and (1-4C)alkyl;R⁹ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl, and—S(O)p(1-4C)alkyl;R¹⁰ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl, benzyl, and(1-4C)alkylsulfonyl;p is (independently at each occurrence) 0, 1 or 2.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, but-2-yl, cyclopentyl,1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, tetrahydrofuryl,tetrahydropyranyl, 1-methoxyprop-2-yl, 2-hydroxyprop-1-yl,2-methoxyprop-1-yl, 2-hydroxybut-1-yl, 2-methoxybut-1-yl,1-fluoromethoxyprop-2-yl and 1,1-difluoromethoxyprop-2-yl;HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing anitrogen atom in the 2-position and optionally 1 or 2 further ringheteroatoms independently selected from O, N and S; which ring isoptionally substituted on any nitrogen atom (provided it is not therebyquaternised) by a methyl, ethyl or isopropyl group and/or on 1 or 2available carbon atoms by a methyl, ethyl or fluoro group;HET-2 is a 5- or 6-membered heteroaryl ring, containing 1, 2 or 3 ringhetereoatoms independently selected from O, S and N; which ring issubstituted on an available carbon atom by a substituent selected fromR², and is optionally further substituted on 1 or 2 available carbonatoms by a substituent independently selected from R³ and/or on anavailable nitrogen atom (provided it is not thereby quaternised) by asubstituent selected from R¹⁰;R² is selected from —C(O)NR⁴R⁵ and —SO₂NR⁴R⁵;R³ is selected from methyl and halo;R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a 4 to 7 membered saturated or partially unsaturated heterocyclylring, optionally containing 1 or 2 further heteroatoms (in addition tothe linking N atom) independently selected from O, N and S, wherein a—CH₂— group can optionally be replaced by a —C(O)— and wherein a sulphuratom in the ring may optionally be oxidised to a S(O) or S(O)₂ group;which ring is optionally substituted on an available carbon atom by 1 or2 substituents independently selected from R⁸ and/or on an availablenitrogen atom by a substituent selected from R⁹;R⁸ is selected from hydroxy, (1-4C)alkoxy and (1-4C)alkyl;R⁹ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl, and—S(O)p(1-4C)alkyl;R¹⁰ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl, benzyl, and(1-4C)alkylsulfonyl;p is (independently at each occurrence) 0, 1 or 2.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, but-2-yl, cyclopentyl,1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, tetrahydrofuryl,tetrahydropyranyl, 1-methoxyprop-2-yl, 2-hydroxyprop-1-yl,2-methoxyprop-1-yl, 2-hydroxybut-1-yl, 2-methoxybut-1-yl,1-fluoromethoxyprop-2-yl and 1,1-difluoromethoxyprop-2-yl;HET-1 is a 5- or 6-membered, C-linked heteroaryl ring containing anitrogen atom in the 2-position and optionally 1 or 2 further ringheteroatoms independently selected from O, N and S; which ring isoptionally substituted on any nitrogen atom (provided it is not therebyquaternised) by a methyl, ethyl or isopropyl group and/or on 1 or 2available carbon atoms by a methyl, ethyl or fluoro group; HET-2 is a 5-or 6-membered heteroaryl ring, containing 1, 2 or 3 ring hetereoatomsindependently selected from O, S and N; which ring is substituted on anavailable carbon atom by a substituent selected from R², and isoptionally further substituted on 1 or 2 available carbon atoms by asubstituent independently selected from R³;R² is selected from —C(O)NR⁴R⁵ and —SO₂NR⁴R⁵;R³ is selected from methyl and halo;R⁴ and R⁵ together with the nitrogen atom to which they are attachedform a 4 to 7 membered saturated or partially unsaturated heterocyclylring, optionally containing 1 or 2 further heteroatoms (in addition tothe linking N atom) independently selected from O, N and S, wherein a—CH₂— group can optionally be replaced by a —C(O)— and wherein a sulphuratom in the ring may optionally be oxidised to a S(O) or S(O)₂ group; orR⁴ and R⁵ together with the nitrogen atom to which they are attachedform a 6-10 membered bicyclic saturated or partially unsaturatedheterocyclyl ring, optionally containing 1 further nitrogen atom (inaddition to the linking N atom), wherein a —CH₂— group can optionally bereplaced by a —C(O)—.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, but-2-yl, 1,3-difluoroprop-2-yl,1-hydroxyprop-2-yl and 1-methoxyprop-2-yl and tetrahydrofuryl;HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;HET-2 is a substituted 5- or 6-membered heteroaryl ring as hereinbeforedefined;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl,tetrahydrofuryl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;HET-2 is a substituted 5- or 6-membered heteroaryl ring as hereinbeforedefined;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;HET-2 is a substituted 5- or 6-membered heteroaryl ring as hereinbeforedefined;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl or pyrrolidinyl ring.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, 1,3-difluoroprop-2-yl, 1-hydroxyprop-2-yland 1-methoxyprop-2-yl,HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl,wherein R¹ is optionally substituted on carbon or nitrogen with a methylor ethyl group;HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and thienyl,substituted by R² and optionally substituted by R³;R³ is fluoro or chloro;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl,tetrahydrofuryl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl,wherein R¹ is optionally substituted with a methyl, isopropyl or ethylgroup;HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and pyrimidinyl,substituted by R² and optionally substituted by R³;R³ is fluoro or chloro;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl, pyridyl,isoxazolyl and pyrazinyl, wherein R¹ is optionally substituted with amethyl, isopropyl or ethyl group and/or (on a carbon atom) by fluoro;HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl, thiazolyl andpyrimidinyl, substituted by R² and optionally substituted by R³;R³ is fluoro or chloro;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl or pyrrolidinyl ring.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl, pyridyl,isoxazolyl and pyrazinyl, wherein R¹ is optionally substituted with amethyl, isopropyl or ethyl group and/or (on a carbon atom) by fluoro;HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl, thiazolyl andpyrimidinyl, substituted by R² and optionally substituted by R³;R³ is methyl, fluoro or chloro;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, 7-azabicyclo[2.2.1]hept-7-yl,morpholino, or pyrrolidinyl ring.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl, pyridyl,isoxazolyl and pyrazinyl, wherein R¹ is optionally substituted with amethyl, isopropyl or ethyl group and/or (on a carbon atom) by fluoro;HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl, thiazolyl andpyrimidinyl, substituted by R² and optionally substituted by R³;R³ is methyl, fluoro or chloro;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl or pyrrolidinyl ring.

In another aspect of the invention there is provided a compound offormula (I) or (IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl, pyridyl,isoxazolyl and pyrazinyl, wherein R¹ is optionally substituted on anitrogen atom with methyl, difluoromethyl, isopropyl or ethyl and/or ona carbon atom by fluoro or methyl; provided that when HET-1 ispyrazolyl, R¹ is selected from 1-methoxyprop-2-yl, isopropyl, andtetrahydrofuryl;HET-2 is selected from pyridyl, pyrazinyl, pyridazinyl, thiazolyl andpyrimidinyl, substituted by R² and optionally substituted by R³;R³ is methyl, fluoro or chloro;R² is —CONR⁴R⁵ or —SO₂NR⁴R⁵, particularly —CONR⁴R⁵;R⁴ and R⁵ together form an azetidinyl, 7-azabicyclo[2.2.1]hept-7-yl,morpholino, or pyrrolidinyl ring.

In another aspect, Aspect A, of the invention there is provided acompound of formula (I) or (IA) as hereinbefore defined, or a saltthereof, wherein:

R¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is selected from pyrazinyl (optionally substituted with methyl),pyrazolyl (optionally substituted on carbon by methyl),methylthiadiazolyl (particularly 3-methyl-1,2,4-thiadiazol-5-yl),thiazolyl (optionally substituted with methyl), pyridyl (optionallysubstituted by fluoro) and isoxazolyl; provided that when HET-1 ispyrazolyl, particularly R¹ is selected from 1-methoxyprop-2-yl,isopropyl, and tetrahydrofuryl; HET-2 is selected from pyridyl,pyrazinyl, pyridazinyl, thiazolyl and pyrimidinyl, substituted by R² andoptionally substituted by R³;R³ is methyl, fluoro or chloro;R² is —CONR⁴R⁵ or —SO₂NR⁴R⁵, particularly —CONR⁴R⁵;R⁴ and R⁵ together form an azetidinyl, 7-azabicyclo[2.2.1]hept-7-yl,morpholino, or pyrrolidinyl ring.

In another aspect, Aspect B, of the invention there is provided acompound of formula (I) or (IA) as hereinbefore defined, or a saltthereof, wherein:

R¹ is selected from isopropyl, cyclopentyl, 1,3-difluoroprop-2-yl,but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is selected from pyrazinyl (optionally substituted with methyl),pyrazolyl (optionally substituted on carbon by methyl),methylthiadiazolyl (particularly 3-methyl-1,2,4-thiadiazol-5-yl),thiazolyl (optionally substituted with methyl), pyridyl (optionallysubstituted by fluoro) and isoxazolyl; provided that when HET-1 ispyrazolyl, particularly R¹ is selected from 1-methoxyprop-2-yl,isopropyl, and tetrahydrofuryl;HET-2 is selected from pyridyl and pyrazinyl, substituted by R² andoptionally substituted by R³;R³ is methyl, fluoro or chloro;R² is —CONR⁴R⁵ or —SO₂NR⁴R⁵, particularly —CONR⁴R⁵;R⁴ and R⁵ together form an azetidinyl or pyrrolidinyl ring, particularlyazetidinyl. Particular compounds of Aspect B are those of formulae (IB),(IC) and/or (ID).

In another aspect, Aspect C, of the invention there is provided acompound of formula (IB), (IC) or (ID) as hereinbefore defined, or asalt thereof, wherein:

R¹ is selected from isopropyl, 1-hydroxyprop-2-yl, tetrahydrofuryl and1-methoxyprop-2-yl; (particularly R¹ is selected from isopropyl,(2S)-1-hydroxyprop-2-yl, tetrahydrofuryl and (2S)-1-methoxyprop-2-yl);HET-1 is methylpyrazinyl;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl ring.

In another aspect, Aspect D, of the invention there is provided acompound of formula (IB) as hereinbefore defined, or a salt thereof,wherein:

R¹ is selected from isopropyl, 1-hydroxyprop-2-yl, tetrahydrofuryl and1-methoxyprop-2-yl; (particularly R¹ is selected from isopropyl,(2S)-1-hydroxyprop-2-yl, tetrahydrofuryl and (2S)-1-methoxyprop-2-yl);HET-1 is methylpyrazinyl;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl ring.

In another aspect, Aspect E, of the invention there is provided acompound of formula (IB), (IC) or (ID) as hereinbefore defined, or asalt thereof, wherein:

R¹ is selected from isopropyl, tetrahydrofuryl and 1-methoxyprop-2-yl(particularly (2S)-1-methoxyprop-2-yl);HET-1 is pyrazolyl;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl ring.

In another aspect, Aspect F, of the invention there is provided acompound of formula (IB) as hereinbefore defined, or a salt thereof,wherein:

R¹ is selected from isopropyl, tetrahydrofuryl and 1-methoxyprop-2-yl(particularly (2S)-1-methoxyprop-2-yl);HET-1 is pyrazolyl;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl ring.

In another aspect of the invention there is provided a compound offormula (I) (or IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, but-2-yl, 1,3-difluoroprop-2-yl,1-hydroxyprop-2-yl and 1-methoxyprop-2-yl and tetrahydrofuryl;HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;HET-2 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;

R² is —SO₂NR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) (or IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, 1,3-difluoroprop-2-yl, 1-hydroxyprop-2-yland 1-methoxyprop-2-yl,HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl,wherein R¹ is optionally substituted on carbon or nitrogen with a methylor ethyl group;HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and thienyl,substituted by R² and optionally substituted by R³;R³ is fluoro or chloro,

R² is —SO₂NR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) (or IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl,tetrahydrofuryl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;HET-2 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;

R² is —SO₂NR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) (or IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl,tetrahydrofuryl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl,wherein R¹ is optionally substituted with a methyl, isopropyl or ethylgroup;HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and pyrimidinyl,substituted by R² and optionally substituted by R³;R³ is fluoro or chloro;

R² is —SO₂NR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) (or IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from isopropyl, 1,3-difluoroprop-2-yl, but-2-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-difluoromethoxyprop-2-yl,tetrahydrofuryl, 1-hydroxybut-2-yl and 1-methoxyprop-2-yl;HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl,wherein R¹ is optionally substituted with a methyl, isopropyl or ethylgroup;HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and pyrimidinyl,substituted by R² and optionally substituted by R³;R³ is fluoro or chloro;

R² is —CONR⁴R⁵ or —SO₂NR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In one aspect of the invention there is provided a compound of formula(I) (or IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from 1-fluoromethoxyprop-2-yl and1,1-difluoromethoxyprop-2-yl;HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;HET-2 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) (or IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from 1-fluoromethoxyprop-2-yl and1,1-difluoromethoxyprop-2-yl;HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl,wherein R¹ is optionally substituted on carbon or nitrogen with a methylor ethyl group;HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and thienyl,substituted by R² and optionally substituted by R³;R³ is fluoro or chloro;

R² is —CONR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In one aspect of the invention there is provided a compound of formula(I) (or IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from 1-fluoromethoxyprop-2-yl and1,1-difluoromethoxyprop-2-yl;HET-1 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;HET-2 is an optionally substituted 5- or 6-membered heteroaryl ring ashereinbefore defined;

R² is —SO₂NR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

In another aspect of the invention there is provided a compound offormula (I) (or IA) as hereinbefore defined, or a salt thereof, wherein:

R¹ is selected from 1-fluoromethoxyprop-2-yl and1,1-difluoromethoxyprop-2-yl;HET-1 is selected from thiazolyl, pyrazolyl, thiadiazolyl and pyrazinyl,wherein R¹ is optionally substituted on carbon or nitrogen with a methylor ethyl group;HET-2 is selected from pyridyl, pyrazinyl, thiazolyl and thienyl,substituted by R² and optionally substituted by R³;R³ is fluoro or chloro;

R² is —SO₂NR⁴R⁵;

R⁴ and R⁵ together form an azetidinyl, pyrrolidinyl or morpholino ring.

Further preferred compounds of the invention are each of the Examples(and salts thereof), each of which provides a further independent aspectof the invention. In further aspects, the present invention alsocomprises any two or more compounds of the Examples (and salts thereof).

Particular compounds of the invention include any one or more of:

-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;-   3-{[5-(azetidin-1-ylsulfonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[3-chloro-5-(morpholin-4-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;    and-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;    and/or    3-{[5-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[2-(azetidin-1-ylcarbonyl)pyrimidin-5-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[2-(azetidin-1-ylcarbonyl)pyrimidin-5-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[4-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[4-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;    and/or    3-{[2-(azetidin-1-ylcarbonyl)pyrimidin-5-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-(cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-(cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-(cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[4-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyridin-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1-methylethyl)oxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1-methylethyl)oxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1-methylethyl)oxy]benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyridin-2-ylbenzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-isoxazol-3-yl-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3-ylbenzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridazin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(4-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-1H-pyrazol-3-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(4-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-1H-pyrazol-3-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-fluoropyridin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[3-chloro-5-(pyrrolidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[3-chloro-5-(pyrrolidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[3-chloro-5-(pyrrolidin-1-ylcarbonyl)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;    and-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide;    and/or    3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-isoxazol-3-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-pyrazin-2-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(5-fluoropyridin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyridin-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-isoxazol-3-yl-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(4-methyl-1,3-thiazol-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methyl-1,3-thiazol-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyrazin-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-pyrazin-2-ylbenzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyrazin-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-pyrazin-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyrazin-2-ylbenzamide;-   3-{[3-chloro-5-(morpholin-4-ylcarbonyl)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;    and-   3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;    and/or-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-pyrazin-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-pyridin-2-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;-   N-(1-methyl-1H-pyrazol-3-yl)-3-{[6-(pyrrolidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-pyrazin-2-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-1H-pyrazol-3-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(5-methyl-1H-pyrazol-3-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-1H-pyrazol-3-ylbenzamide;-   3-{[5-(azetidin-1-ylsulfonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;-   3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;    and/or    3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;-   3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;    or a salt thereof.

A further feature of the invention is a pharmaceutical compositioncomprising a compound of Formula (I), (IA), (IB), (IC) or (ID) asdefined above, or a pharmaceutically-acceptable salt thereof, togetherwith a pharmaceutically-acceptable diluent or carrier.

According to another aspect of the invention there is provided the acompound of Formula (I), (IA), (IB), (IC) or (ID) or apharmaceutically-acceptable salt thereof as defined above for use as amedicament.

According to another aspect of the invention there is provided the acompound of Formula (I), (IA), (IB), (IC) or (ID) or apharmaceutically-acceptable salt thereof as defined above for use as amedicament for treatment of a disease mediated through GLK, inparticular type 2 diabetes.

Further according to the invention there is provided the use a compoundof Formula (I), (IA), (IB), (IC) or (ID) or apharmaceutically-acceptable salt thereof in the preparation of amedicament for treatment of a disease mediated through GLK, inparticular type 2 diabetes.

The compound is suitably formulated as a pharmaceutical composition foruse in this way.

According to another aspect of the present invention there is provided amethod of treating GLK mediated diseases, especially diabetes, byadministering an effective amount of a compound of Formula (I), (IA),(IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof, to amammal in need of such treatment.

Specific diseases which may be treated by a compound or composition ofthe invention include: blood glucose lowering in Type 2 DiabetesMellitus without a serious risk of hypoglycemia (and potential to treattype 1), dyslipidemia, obesity, insulin resistance, metabolic syndromeX, impaired glucose tolerance.

As discussed above, thus the GLKIGLKRP system can be described as apotential “Diabesity” target (of benefit in both Diabetes and Obesity).Thus, according to another aspect of the invention there is provided theuse of a compound of Formula (I), (IA), (IB), (IC) or (ID) or apharmaceutically-acceptable salt thereof, in the preparation of amedicament for use in the combined treatment or prevention, particularlytreatment of diabetes and obesity.

According to another aspect of the invention there is provided the useof a compound of Formula (I), (IA), (IB), (IC) or (ID) or apharmaceutically-acceptable salt thereof, in the preparation of amedicament for use in the treatment or prevention, particularlytreatment of obesity.

According to another aspect of the invention there is provided the acompound of Formula (I), (IA), (IB), (IC) or (ID) or apharmaceutically-acceptable salt thereof as defined above for use as amedicament for treatment or prevention, particularly treatment ofobesity.

According to a further aspect of the invention there is provided amethod for the combined treatment of obesity and diabetes byadministering an effective amount of a compound of Formula (I), (IA),(IB), (IC) or (ID) or a pharmaceutically-acceptable salt thereof, to amammal in need of such treatment.

According to a further aspect of the invention there is provided amethod for the treatment of obesity by administering an effective amountof a compound of Formula (I), (IA), (IB), (IC) or (ID) or apharmaceutically-acceptable salt thereof, to a mammal in need of suchtreatment.

Compounds of the invention may be particularly suitable for use aspharmaceuticals because of advantageous physical and/or pharmacokineticproperties, and/or favourable toxicity profile and/or favourablemetabolic profile.

Favourable toxicity profile may be demonstrated, for example, by use ofan Ames test assay, and/or by testing against the HERG ion channel. Afavourable metabolic profile may mean, for example, reduced rate ofmetabolism, leading to reduction in clearance of the compound from thebody and hence increased exposure to the compound, or a favourablemetabolic profile may mean, for example, not forming active metabolites(which might be considered undesirable in some circumstances).

For example, compounds of Aspects A to F may have favourabletoxicological profiles.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing). Dosageforms suitable for oral use are preferred.

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula (I), (IA), (IB), (IC) or (ID) will naturallyvary according to the nature and severity of the conditions, the age andsex of the animal or patient and the route of administration, accordingto well known principles of medicine.

In using a compound of the Formula (I), (IA), (IB), (IC) or (ID) fortherapeutic or prophylactic purposes it will generally be administeredso that a daily dose in the range, for example, 0.5 mg to 75 mg per kgbody weight is received, given if required in divided doses. In generallower doses will be administered when a parenteral route is employed.Thus, for example, for intravenous administration, a dose in the range,for example, 0.5 mg to 30 mg per kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.5 mg to 25 mg per kg body weight will be used. Oraladministration is however preferred.

The elevation of GLK activity described herein may be applied as a soletherapy or in combination with one or more other substances and/ortreatments for the indication being treated. Such conjoint treatment maybe achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment.Simultaneous treatment may be in a single tablet or in separate tablets.For example in the treatment of diabetes mellitus, chemotherapy mayinclude the following main categories of treatment:

1) Insulin and insulin analogues;2) Insulin secretagogues including sulphonylureas (for exampleglibenclamide, glipizide), prandial glucose regulators (for examplerepaglinide, nateglinide);3) Agents that improve incretin action (for example dipeptidyl peptidaseIV inhibitors, and GLP-1 agonists);4) Insulin sensitising agents including PPARgamma agonists (for examplepioglitazone and rosiglitazone), and agents with combined PPARalpha andgamma activity;5) Agents that modulate hepatic glucose balance (for example metformin,fructose 1, 6 bisphosphatase inhibitors, glycogen phopsphorylaseinhibitors, glycogen synthase kinase inhibitors);6) Agents designed to reduce the absorption of glucose from theintestine (for example acarbose);7) Agents that prevent the reabsorption of glucose by the kidney (SGLTinhibitors);8) Agents designed to treat the complications of prolongedhyperglycaemia (for example aldose reductase inhibitors);9) Anti-obesity agents (for example sibutramine and orlistat);10) Anti-dyslipidaemia agents such as, HMG-CoA reductase inhibitors (egstatins); PPARα agonists (fibrates, eg gemfibrozil); bile acidsequestrants (cholestyramine); cholesterol absorption inhibitors (plantstanols, synthetic inhibitors); bile acid absorption inhibitors (IBATi)and nicotinic acid and analogues (niacin and slow release formulations);11) Antihypertensive agents such as, β blockers (eg atenolol, inderal);ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine);Angiotensin receptor antagonists (eg candesartan), α antagonists anddiuretic agents (eg. furosemide, benzthiazide);12) Haemostasis modulators such as, antithrombotics, activators offibrinolysis and antiplatelet agents; thrombin antagonists; factor Xainhibitors; factor VIIa inhibitors); antiplatelet agents (eg. aspirin,clopidogrel); anticoagulants (heparin and Low molecular weightanalogues, hirudin) and warfarin;13) Agents which antagonise the actions of glucagon; and14) Anti-inflammatory agents, such as non-steroidal anti-inflammatorydrugs (eg. aspirin) and steroidal anti-inflammatory agents (eg.cortisone).

According to another aspect of the present invention there is providedindividual compounds produced as end products in the Examples set outbelow and salts thereof.

A compound of the invention, or a salt thereof, may be prepared by anyprocess known to be applicable to the preparation of such compounds orstructurally related compounds. Functional groups may be protected anddeprotected using conventional methods. For examples of protectinggroups such as amino and carboxylic acid protecting groups (as well asmeans of formation and eventual deprotection), see T. W. Greene and P.G. M. Wuts, “Protective Groups in Organic Synthesis”, Second Edition,John Wiley & Sons, New York, 1991.

Processes for the synthesis of compounds of Formula (I), (IA), (IB),(IC) or (ID) are provided as a further feature of the invention. Thus,according to a further aspect of the invention there is provided aprocess for the preparation of a compound of Formula (I), (IA), (IB),(IC) or (ID), which comprises a process a) to e) (wherein the variablesare as defined hereinbefore for compounds of Formula (I), (IA), (IB),(IC) or (ID) unless otherwise defined):

-   (a) reaction of an acid of Formula (III) or activated derivative    thereof with a compound of Formula (IV), wherein R¹ is as    hereinbefore defined or a protected version thereof;

-    or-   (b) reaction of a compound of Formula (V) with a compound of Formula    (VI),

wherein X¹ is a leaving group and X² is a hydroxyl group or X¹ is ahydroxyl group and X² is a leaving group, and wherein R¹ is ashereinbefore defined or a protected version thereof;process (b) could also be accomplished using the intermediate esterFormula (VII), wherein P¹ is a protecting group as hereinafterdescribed, followed by ester hydrolysis and amide formation byprocedures described elsewhere and well known to those skilled in theart;

-    or-   (c) reaction of a compound of Formula (VIII) with a compound of    Formula (IX)

wherein X³ is a leaving group or an organometallic reagent and X⁴ is ahydroxyl group or X³ is a hydroxyl group and X⁴ is a leaving group or anorganometallic reagent, and wherein R¹ is as hereinbefore defined or aprotected version thereof; process (c) could also be accomplished usingthe intermediate ester Formula (X), followed by ester hydrolysis andamide formation by procedures described elsewhere and well known tothose skilled in the art;

-   (d) reaction of a compound of Formula (X¹) with a compound of    Formula (XII),

wherein X⁵ is a leaving group; and wherein R¹ is as hereinbefore definedor a protected version thereof; or

-   e) reaction of a compound of formula (XIII)

wherein R^(2a) is a precursor to R¹, such as a carboxylic acid, ester oranhydride (for R²=—CONR⁴R⁵) or the sulfonic acid equivalents (for R² is—SO²NR⁴R⁵); with an amine of formula —NR⁴R⁵;and thereafter, if necessary:i) converting a compound of Formula (I) into another compound of Formula(I);ii) removing any protecting groups; and/oriii) forming a salt thereof.

Suitable leaving groups X¹ to X⁵ for processes b) to d) are any leavinggroup known in the art for these types of reactions, for example halo,alkoxy, trifluoromethanesulfonyloxy, methanesulfonyloxy, orp-toluenesulfonyloxy; or a group (such as a hydroxy group) that may beconverted into a leaving group (such as an oxytriphenylphosphoniumgroup) in situ.

Suitable values for R¹ containing a protected hydroxy group are anysuitable protected hydroxy group known in the art, for example simpleethers such as a methyl ether, tert-butyl ether or silylethers such as—OSi[(1-4C)alkyl]₃ (wherein each (1-4C)alkyl group is independentlyselected from methyl, ethyl, propyl, isopropyl, and tertbutyl). Examplesof such trialkylsilyl groups are trimethylsilyl, triethylsilyl,triisopropylsilyl and tert-butyldimethylsilyl. Further suitable silylethers are those containing phenyl and substituted phenyl groups, suchas —Si(PhMe₂) and —Si(TolMe₂) (wherein Tol=methylbenzene). Furthersuitable values for hydroxy protecting groups are given hereinafter.

Compounds of Formulae (III) to (XII) are commercially available, or areknown in the art, or may be made by processes known in the art, forexample as shown in the accompanying Examples, or as described below.For further information on processes for making such compounds, we referto our PCT publications WO 03/000267, WO 03/015774 and WO 03/000262 andreferences therein. In general it will be appreciated that any aryl-O oralkyl-O bond may be formed by nucleophilic substitution or metalcatalysed processes, optionally in the presence of a suitable base.

Compounds of Formula (XIII) may be made by processes such as those shownin processes a) to d) and/or by those processes mentioned above forcompounds of formulae (III) to (XII).

The group R¹ in the compounds of formulae (III), (IX), (X), (X¹) and(XIII) may be made by reaction of suitable precursors with compounds offormula (V) or derivatives thereof, depending on the nature of the R¹group, for example, by nucleophilic displacement of a leaving group X¹in a compound of formula (V). Compounds of formula (V) are generallycommercially available or maybe made by simple functional groupinterconversions from commercially available compounds, or by literaturemethods. Further information is available in WO2004/076420,WO2005/054200, WO2005/054233, WO 2005/044801 and WO 2005/056530. Someillustrative examples using various R¹ groups are given in the Schemesbelow, and/or in the accompanying examples, and may generally be appliedanalogously to R¹ groups not shown below by methods known in the art,see for example Bull. Chem. Soc. Japan, 73 (2000), 471-484,International Patent Application WO 2002/050003 and Bioorganic andMedicinal Chemistry Letters, (2001), 11, 407.

[PG is protecting group, Ts is p-toluenesulfonyl].

Examples of conversions of a compound of Formula (I) into anothercompound of Formula (I), well known to those skilled in the art, includefunctional group interconversions such as hydrolysis, hydrogenation,hydrogenolysis, oxidation or reduction, and/or further functionalisationby standard reactions such as amide or metal-catalysed coupling, ornucleophilic displacement reactions. Further examples of a conversion ofa compound of Formula (I) into another compound of Formula (I) ismethylation of a hydroxy group in R¹ to give a methoxy group, andconversion of, for example, a hydroxymethyl group in R¹ (such as when R¹is hydroxyprop-2-yl) into a difluoromethoxy group, using reactions suchas those as illustrated in Scheme 4.

It will be understood that substituents R³, R⁶ and/or R⁷ may beintroduced into the molecule at any convenient point in the syntheticsequence or may be present in the starting materials. A precursor to oneof these substituents may be present in the molecule during the processsteps a) to e) above, and then be transformed into the desiredsubstituent as a final step to form the compound of formula (I);followed where necessary by

i) converting a compound of Formula (I) into another compound of Formula(I);ii) removing any protecting groups; and/oriii) forming a salt thereof.

Specific reaction conditions for the above reactions are as follows,wherein when P¹ is a protecting group P¹ is preferably (1-4C)alkyl, forexample methyl or ethyl:

Process a)—coupling reactions of amino groups with carboxylic acids toform an amide are well known in the art. For example,(i) using an appropriate coupling reaction, such as a carbodiimidecoupling reaction performed with EDAC(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) in thepresence of dimethylaminopyridine (DMAP) in a suitable solvent such asdichloromethane (DCM), chloroform or dimethylformamide (DMF) at roomtemperature; or(ii) reaction in which the carboxylic group is activated to an acidchloride by reaction with oxalyl chloride in the presence of a suitablesolvent such as DCM. The acid chloride can then be reacted with acompound of Formula (IV) in the presence of a base, such astriethylamine or pyridine, in a suitable solvent such as chloroform orDCM at a temperature between 0° C. and 80° C.Process b)—compounds of Formula (V) and (VI) can be reacted together ina suitable solvent, such as DMF or tetrahydrofuran (THF), with a basesuch as sodium hydride or potassium tert-butoxide, at a temperature inthe range 0 to 200° C., optionally using microwave heating or metalcatalysis such as palladium(II)acetate, palladium on carbon,copper(II)acetate or copper(I) iodide; alternatively, compounds ofFormula (V) and (VI) can be reacted together in a suitable solvent, suchas THF or DCM, with a suitable phosphine such as triphenylphosphine, andazodicarboxylate such as diethylazodicarboxylate; process b) could alsobe carried out using a precursor to the ester of formula (VII) such asan aryl-nitrile or trifluoromethyl derivative, followed by conversion toa carboxylic acid and amide formation as previously described;Process c)—compounds of Formula (VIII) and (IX) can be reacted togetherin a suitable solvent, such as DMF or THF, with a base such as sodiumhydride or potassium tert-butoxide, at a temperature in the range 0 to200° C., optionally using microwave heating or metal catalysis such aspalladium(II)acetate, palladium on carbon, copper(II)acetate orcopper(I)iodide; process c) could also be carried out using a precursorto the ester of formula (X) such as an aryl-nitrile or trifluoromethylderivative, followed by conversion to a carboxylic acid and amideformation as previously described;compounds of the formula (VIII) are commercially available or can beprepared from commercially available materials by processes well knownto those skilled in the art, for example functional groupinterconversions (such as hydrolysis, hydrogenation, hydrogenolysis,oxidation or reduction), and/or further functionalisation and/orcyclisation by standard reactions (such as amide or sulphonamide ormetal-catalysed coupling, or nucleophilic displacement or electrophilicsubstitution reactions);Process d)—reaction of a compound of Formula (XI) with a compound ofFormula (XII) can be performed in a polar solvent, such as DMF or anon-polar solvent such as THF with a strong base, such as sodium hydrideor potassium tert-butoxide at a temperature between 0 and 200° C.,optionally using microwave heating or metal catalysis, such aspalladium(II)acetate, palladium on carbon, copper(II)acetate orcopper(I)iodide;Process e)—coupling reactions of amino groups with carboxylic orsulfonic acids or acid derivatives to form an amide are well known inthe art and are described above for Process a).

Certain intermediates of formula (III), (VI), (VII), (IX) and/or (XI)are believed to be novel and comprise an independent aspect of theinvention.

Certain intermediates of formula (III), (IX) and/or (XI) wherein R¹ isas defined herein for a compound of formula (I) are believed to be noveland comprise an independent aspect of the invention.

Certain intermediates of formula (XIII) are believed to be novel andcomprise an independent aspect of the invention.

During the preparation process, it may be advantageous to use aprotecting group for a functional group within the molecule. Protectinggroups may be removed by any convenient method as described in theliterature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Specific examples of protecting groups are given below for the sake ofconvenience, in which “lower” signifies that the group to which it isapplied preferably has 1-4 carbon atoms. It will be understood thatthese examples are not exhaustive. Where specific examples of methodsfor the removal of protecting groups are given below these are similarlynot exhaustive. The use of protecting groups and methods of deprotectionnot specifically mentioned is of course within the scope of theinvention.

A carboxy protecting group may be the residue of an ester-formingaliphatic or araliphatic alcohol or of an ester-forming silanol (thesaid alcohol or silanol preferably containing 1-20 carbon atoms).Examples of carboxy protecting groups include straight or branched chain(1-12C)alkyl groups (e.g. isopropyl, t-butyl); lower alkoxy lower alkylgroups (e.g. methoxymethyl, ethoxymethyl, isobutoxymethyl); loweraliphatic acyloxy lower alkyl groups, (e.g. acetoxymethyl,propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); loweralkoxycarbonyloxy lower alkyl groups (e.g. 1-methoxycarbonyloxyethyl,1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (e.g.p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl andphthalidyl); tri(lower alkyl)silyl groups (e.g. trimethylsilyl andt-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (e.g.trimethylsilylethyl); and (2-6C)alkenyl groups (e.g. allyl andvinylethyl).

Methods particularly appropriate for the removal of carboxyl protectinggroups include for example acid-, metal- or enzymically-catalysedhydrolysis. Hydrogenation may also be used.

Examples of hydroxy protecting groups include methyl, t-butyl, loweralkenyl groups (e.g. allyl); lower alkanoyl groups (e.g. acetyl); loweralkoxycarbonyl groups (e.g. t-butoxycarbonyl); lower alkenyloxycarbonylgroups (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g.benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri loweralkyl/arylsilyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl); tetrahydropyran-2-yl; aryl lower alkyl groups(e.g. benzyl) groups; and triaryl lower alkyl groups (e.g.triphenylmethyl). Examples of amino protecting groups include formyl,aralkyl groups (e.g. benzyl and substituted benzyl, e.g.p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, andtriphenylmethyl); di-p-anisylmethyl and furylmethyl groups; loweralkoxycarbonyl (e.g. t-butoxycarbonyl); lower alkenyloxycarbonyl (e.g.allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g.benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl; trialkylsilyl (e.g. trimethylsilyl andt-butyldimethylsilyl); alkylidene (e.g. methylidene); benzylidene andsubstituted benzylidene groups.

Methods appropriate for removal of hydroxy and amino protecting groupsinclude, for example, hydrogenation, nucleophilic displacement, acid-,base, metal- or enzymically-catalysed hydrolysis, catalytichydrogenolysis or photolytically for groups such aso-nitrobenzyloxycarbonyl, or with fluoride ions for silyl groups. Forexample, methylether protecting groups for hydroxy groups may be removedby trimethylsilyliodide. A tert-butyl ether protecting group for ahydroxy group may be removed by hydrolysis, for example by use ofhydrochloric acid in methanol.

Examples of protecting groups for amide groups include aralkoxymethyl(e.g. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl(e.g. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl(e.g. trimethylsilyl, t-butyldimethylsily, t-butyldiphenylsilyl); trialkyl/arylsilyloxymethyl (e.g. t-butyldimethylsilyloxymethyl,t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (e.g. 4-methoxyphenyl);2,4-di(alkoxy)phenyl (e.g. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (e.g.4-methoxybenzyl); 2,4-di(alkoxy)benzyl (e.g. 2,4-di(methoxy)benzyl); andalk-1-enyl (e.g. allyl, but-1-enyl and substituted vinyl e.g.2-phenylvinyl).

Aralkoxymethyl, groups may be introduced onto the amide group byreacting the latter group with the appropriate aralkoxymethyl chloride,and removed by catalytic hydrogenation. Alkoxymethyl, trialkyl/arylsilyl and tri alkyl/silyloxymethyl groups may be introduced byreacting the amide with the appropriate chloride and removing with acid;or in the case of the silyl containing groups, fluoride ions. Thealkoxyphenyl and alkoxybenzyl groups are conveniently introduced byarylation or alkylation with an appropriate halide and removed byoxidation with ceric ammonium nitrate. Finally alk-1-enyl groups may beintroduced by reacting the amide with the appropriate aldehyde andremoved with acid.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferred aspectsand embodiments of the compounds of the invention described herein alsoapply.

The following examples are for illustration purposes and are notintended to limit the scope of this application. Each exemplifiedcompound represents a particular and independent aspect of theinvention. In the following non-limiting Examples, unless otherwisestated:

-   -   (i) evaporations were carried out by rotary evaporation in vacuo        and work-up procedures were carried out after removal of        residual solids such as drying agents by filtration;    -   (ii) operations were carried out at room temperature, that is in        the range 18-25° C. and under an atmosphere of an inert gas such        as argon or nitrogen;    -   (iii) yields are given for illustration only and are not        necessarily the maximum attainable;    -   (iv) the structures of the end-products of the Formula (I) were        confirmed by nuclear (generally proton) magnetic resonance (NMR)        with a field strength (for proton) of 300 MHz (generally using a        Varian Gemini 2000) or 400 MHz (generally using a Bruker Avance        DPX400), unless otherwise stated, and mass spectral techniques;        proton magnetic resonance chemical shift values were measured on        the delta scale and peak multiplicities are shown as follows: s,        singlet; d, doublet; t, triplet; m, multiplet; br, broad; q,        quartet, quin, quintet;    -   (v) intermediates were not generally fully characterised and        purity was assessed by thin layer chromatography (TLC),        high-performance liquid chromatography (HPLC), infra-red (IR) or        NMR analysis;    -   (vi) Purification by chromatography generally refers to flash        column chromatography, on silica unless otherwise stated. Column        chromatography was generally carried out using prepacked silica        cartridges (from 4 g up to 400 g) such as Redisep™ (available,        for example, from Presearch Ltd, Hitchin, Herts, UK) or Biotage        (Biotage UK Ltd, Hertford, Herts, UK), eluted using a pump and        fraction collector system. Purification by Solid Phase        Extraction (SPE) methods generally refers to the use of        chromatography cartridges packed with SPE materials such as        ISOLUTE® SCX-2 columns (available, for example, From        International Sorbent Technology Ltd, Dryffryn Business Park,        Hengoed, Mid Glamorgan, UK);    -   (vii) Mass spectra (MS) data was generated on an LCMS system        where the HPLC component comprised generally either a Agilent        1100 or Waters Alliance HT (2790 & 2795) equipment and was run        on a Phemonenex Gemini C18 5 μm, 50×2 mm column (or similar)        eluting with either acidic eluent (for example, using a gradient        between 0-95% water/acetonitrile with 5% of a 1% formic acid in        50:50 water:acetonitrile (v/v) mixture; or using an equivalent        solvent system with methanol instead of acetonitrile), or basic        eluent (for example, using a gradient between 0-95%        water/acetonitrile with 5% of a 0.1% 880 Ammonia in acetonitrile        mixture); and the MS component comprised generally a Waters ZQ        spectrometer. Chromatograms for Electrospray (ESI) positive and        negative Base Peak Intensity, and UV Total Absorption        Chromatogram from 220-300 nm, are generated and values for m/z        are given; generally, only ions which indicate the parent mass        are reported and unless otherwise stated the value quoted is        (M−H)⁻;    -   (viii) Suitable microwave reactors include “Smith Creator”, “CEM        Explorer”, “Biotage Initiator sixty” and “Biotage Initiator        eight”.    -   (ix) Melting points were generally carried out by Differential        Scanning Calorimetry (DSC); analysis was generally conducted        using equipment such as a Mettler DSC822e or a Mettler DSC820.        Samples of typically less than 5 mg of material, contained in a        40 μL aluminum pan fitted with a pierced lid, were heated over        the temperature range 25° C. to 325° C. at a constant heating        rate of 10° C. per minute. A purge gas using nitrogen was used        at a flow rate of 100 mL per minute. It will be understood that        the onset and/or peak temperature values of the DSC may vary        slightly from one machine to another, one method to another or        from one sample to another, and so the values quoted are not to        be construed as absolute. It will be appreciated that some        samples may be solvates and that this may also affect melting        points.

Abbreviations

-   DCM dichloromethane-   DEAD diethylazodicarboxylate-   DIAD diisopropylazodicarboxylate-   DIPEA N,N-Diisopropylethylamine-   DMA dimethylacetamide-   DMSO dimethyl sulphoxide-   DMF dimethylformamide-   EDAC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexofluorophosphate-   HPLC high pressure liquid chromatography-   HPMC Hydroxypropylmethylcellulose-   LCMS liquid chromatography/mass spectroscopy-   NMP N-methyl-2-pyrrolidone-   NMR nuclear magnetic resonance spectroscopy-   RT room temperature-   THF tetrahydrofuran-   TFA trifluoroacetic acid-   CDCl₃ deuterochloroform-   MgSO₄ magnesium sulfate-   NaHMDS sodium hexamethyldisilazide

All compound names were derived using ACD NAME computer package.

EXAMPLE 13-{[5-(Azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1,3-thiazol-2-ylbenzamide

A mixture of3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide(0.15 g, 0.33 mmol) in methanol (10 mL) and 1M hydrochloric acid (10 mL)was stirred for 90 mins at RT. The volatiles were removed in vacuo andthe residue taken to pH6 with saturated aqueous sodium bicarbonatesolution then extracted into ethyl acetate (3×30 mL) and the combinedorganic layers washed with water (30 mL), brine (30 mL), dried (MgSO₄),filtered and the solvents removed in vacuo to a residue which waschromatographed on silica eluting with a gradient of 0-10% methanol inethyl acetate to give the desired compound (65 mg).

¹H NMR δ (CDCl₃): 1.32 (d, 3H), 2.30 (s, 1H), 2.39 (quin, 2H), 3.79 (m,2H), 4.20-4.40 (brm, 4H), 4.58 (m, 1H), 6.98 (m, 2H), 7.27 (m, 1H), 7.35(m, 1H), 7.39 (s, 1H), 7.41 (s, 1H), 8.11 (d, 1H), 8.41 (s, 1H), 11.50(s, 1H). m/z 455 (M+H)⁺

The following compounds were synthesised in an analogous fashion fromthe appropriate silyl ether.

Example Structure m/z NMR 1a

489, 491(M + H)⁺ ¹H NMR δ (CDC1₃): 1.35 (d, 3H), 2.25 (s,1H), 2.43(quin, 2H), 3.77 (m, 2H), 4.20-4.40 (brm, 4H), 4.59 (m, 1H), 6.95 (d,1H),7.03 (s, 1H), 7.31 (d, 1H), 7.39 (s, 1H), 7.47(s, 1H), 8.17 (s, 1H),8.27 (s, 1H), 11.60(brs, 1H). 1b

455(M + H)⁺ ¹H NMR δ (CDC1₃): 1.22 (d, 3H), 2.38 (m,3H), 3.68 (m, 2H),4.19 (t, 2H), 4.48 (m,1H), 4.63 (t, 2H), 6.75 (m, 1H), 6.91 (d,1H), 7.13(s, 1H), 7.19 (m, 1H), 7.28 (m,2H), 8.03 (d, 1H), 8.22 (s, 1H), 11.40(brs, 1H). 1c

452(M + H)⁺ ¹H NMR δ (CDCl₃): 1.33 (d, 3H), 2.40(quin, 2H), 3.78 (m,2H), 3.82 (s, 3H), 4.25(t, 2H), 4.37 (t, 2H), 4.57 (sextet, 1H), 6.80(d,2H), 7.11 (s, 1H), 7.28 (m, 2H), 7.63 (s,1H), 8.52 (s, 1H), 8.61 (s, 2H)1d

452(M + H)⁺ ¹H NMR δ (CDC1₃): 1.28 (d, 3H), 2.26(quin, 2H), 2.48 (t,1H), 3.67 (m, 2H), 3.69(s, 3H), 4.18 (t, 2H), 4.45 (sextet, 1H), 4.63(t,2H), 6.70 9m, 2H), 7.05 (m, 1H), 7.20(m, 2H), 7.28 (m, 1H), 8.02 (d,1H), 8.21(d, 1H), 8.73 (s, 1H)

The preparation of3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamideused in Example 1 is described below:

3-{[5-(Azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide

Potassium carbonate (0.14 g, 0.98 mmol) was added to a mixture of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-1,3-thiazol-2-ylbenzamide(200 mg, 0.49 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (96mg, 0.49 mmol) in acetonitrile (5.0 mL) and the stirred mixture heatedat 160° C. in a ‘Biotage initiator Microwave’ for 4 hours. The mixturewas allowed to reach RT and pressure and was partitioned between ethylacetate (50 mL) and water (50 mL). The ethyl acetate layer wasseparated, washed with water (5×50 mL), brine (50 mL), dried (MgSO₄) andevaporated to a residue which was chromatographed on silica, elutingwith a gradient of 60-100% ethyl acetate in isohexane, to give thedesired compound. (0.15 g).

m/z 569 (M+H)⁺

The precursor for Example 1a was prepared in a similar fashion from3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-1,3-thiazol-2-ylbenzamideusing 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine:

Structure m/z NMR

603, 605(M + H)⁺ ¹H NMR δ (CDCl₃): 0.00 (s, 3H), 0.03 (s, 3H), 0.81(s,9H), 1.27 (d, 3H), 2.32 (quin, 2H), 3.60-3.80 (m, 2H),4.15-4.35 (brm,4H), 4.45 (m, 1H), 6.83 (d, 1H), 6.95 (m,1H), 7.19 (d, 1H), 7.25 (s,1H), 7.30 (s, 1H), 8.08 (d, 1H),8.17 (d, 1H), 11.95 (brs, 1H).

The precursor for Example 1b was prepared as described below:

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide

Cesium carbonate (0.478 g, 1.47 mmol) was added to a mixture of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-1,3-thiazol-2-ylbenzamide(200 mg, 0.49 mmol), bromotris(triphenylphosphine)copper (46 mg, 0.049mmol) and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (130 mg, 5.39 mmol)in DMA (5.0 mL) and the stirred mixture heated at 160° C. in a ‘Biotageinitiator Microwave’ for 3 hours. The mixture was allowed to reach RTand pressure and was partitioned between ethyl acetate (50 mL) and water(50 mL). The ethyl acetate layer was separated, washed with water (5×50mL), brine (50 mL), dried (MgSO₄) and evaporated to a residue which waschromatographed on silica, eluting with a gradient of 0-100% ethylacetate in isohexane, to give the desired compound. (47 mg).

¹H NMR δ (CDCl₃): 0.00 (s, 3H), 0.03 (s, 3H), 0.83 (s, 9H), 1.29 (d,3H), 2.32 (quin, 2H), 3.65-3.80 (m, 2H), 4.21 (t, 2H), 4.46 (m, 1H),4.68 (t, 2H), 6.81 (s, 1H), 6.92 (m, 1H), 7.25 (m, 1H), 7.30-7.50 (m,2H), 7.65 (m, 1H), 8.08 (d, 1H), 8.28 (s, 1H), 11.50 (brs, 1H).

m/z 569 (M+H)⁺

The precursors for examples 1c-1d were prepared in a similar fashionfrom3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[((1S)-1-methyl-2-{[tris(1-methylethyl)silyl]oxy}ethyl)oxy]benzamideusing the appropriate bromopyridine:

Structure m/z NMR

608(M + H)⁺

608(M + H)⁺

Bromotris(triphenylphosphine)copper may be prepared according toSynthetic Communications, 31(18), 2865-2879 (2001). The preparation ofbromotris(triphenylphosphine)copper is described below.

Bromotris(triphenylphosphine)copper

Copper (II) bromide (111.7 g, 0.5 mol) was added in portions to astirred solution of triphenylphosphine (557.4 g, 2.13 mol) in methanol(1.85 L) at RT (an exotherm to 32° C. was observed). The reaction wasstirred for 10 minutes then heated to 65° C. and cooled overnight. Thesolid was collected by filtration, washed with ethanol (5 vol), diethylether (3×5 vol), dried on sinter under vacuum for 2 hours, then in avacuum oven at 30° C. overnight to give product as crystalline solid(460 g).

The preparation of 5-(azetidin-1-ylcarbonyl)-2-chloropyridine used inthe preparation of3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide,a precursor to Example 1, is described below:

5-(Azetidin-1-ylcarbonyl)-2-chloropyridine

DMF (2 drops) was added to a solution of 6-chloronicotinic acid (1.00 g,6.35 mmol) and oxalyl chloride (0.67 mL, 7.62 mmol) in DCM (20 mL) and2M hydrogen chloride in ether (3.15 mL, 6.35 mmol). The mixture wasstirred at RT for 4 hours and the DCM and excess oxalyl chlorideevaporated in vacuo. The residual acid chloride was dissolved in DCM (10mL) and added to a mixture of azetidine hydrochloride (0.66 g, 6.99mmol) and triethylamine (2.14 mL, 13.97 mmol) in DCM (10 mL) thenstirred at RT for 24 hours. The DCM was evaporated in vacuo, and theresidue partitioned between ethyl acetate (100 mL) and 1M citric acid(50 mL). The ethyl acetate layer was washed sequentially with saturatedaqueous sodium hydrogen carbonate (50 mL) and brine (50 mL), dried(MgSO₄), and the solvent removed in vacuo to give a residue which waschromatographed on silica, eluting with a gradient of 50-100% ethylacetate in isohexane, to give the desired compound (0.73 g). ¹H NMR δ(CDCl₃) 2.43 (quin, 2H), 4.2-4.4 (brm, 4H), 7.42 (d, 1H), 7.97 (d, 1H),8.63 (s, 1H). m/z 197 (M+H)⁺

The halopyridines used in the preparation of precursors for Examples1a-1d were prepared in a similar fashion from the appropriate nicotinicacid:

Structure m/z NMR

¹H NMR δ (CDCl₃): 2.43 (quin, 2H), 4.21-4.44 (m, 4H),8.11 (d, 1H), 8.53(d, 1H)

241, 243(M + H)⁺ ¹H NMR δ (CDCl₃): 2.35 (quin, 2H), 4.25 (t, 2H), 4.70(t,2H), 7.93 (d, 1H), 8.03 (d, 1H), 8.63 (s, 1H).

241, 243(M + H)⁺ ¹H NMR δ (CDCl₃): 2.42 (quin, 2H), 4.20-4.45 (m,4H),8.16 (t, 1H), 8.76 (t, 2H)

The nicotinic acids were either commercially available compounds orcompounds known in the literature. Reference for2-(azetidin-1-ylcarbonyl)-5-bromopyridine (Heterocycles, 15(1) 1981,213-23).

The preparation of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-1,3-thiazol-2-ylbenzamideused in the synthesis of Example 1, 1a and 1b is described below:

3-[((1S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-1,3-thiazol-2-ylbenzamide

An aqueous solution of lithium hydroxide monohydrate (0.304 g, 7.25mmol) was added to a solution of3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide(1.552 g, 2.90 mmol) in THF (40 mL) and stirred at RT overnight. The THFwas removed in vacuo and the residual solution adjusted to pH 7 byaddition of 1N hydrochloric acid (7.25 mL). A gum formed, and thesolution was filtered and the gum dissolved in methanol. The filtratewas partitioned with ethyl acetate (75 mL) and the organics washed withbrine, dried (MgSO₄), combined with the methanol solution and evaporatedto a residue which was chromatographed on silica, eluting with 40% ethylacetate in isohexane, to give the required product (0.865 g)

¹H NMR δ (CDCl₃): −0.02 (d, 6H), 0.81 (s, 9H), 1.24 (d, 3H), 3.67 (m,2H), 4.43 (sextet, 1H), 6.65 (t, 1H), 7.00 (d, 1H), 7.13 (t, 1H), 7.15(t, 1H), 7.40 (d, 1H). m/z 409 (M+H)⁺

3-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide

tert-Butyldimethylsilyl chloride (1.66 g, 11.0 mmol) and imidazole (1.78g, 26.0 mmol) were a to a solution of3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1,3-thiazol-2-ylbenzamide(1.541 g, 5.24 mmol) in DMF (10 mL) and the reaction stirred at RT undera silica drying tube overnight. Water (30 μL) was added and the solutionpartitioned with ethyl acetate (100 mL). The organic phase was washedwith brine, dried (MgSO₄) and evaporated to a residue which waschromatographed on silica, eluting with 15% ethyl acetate in isohexane,to give the required product (1.525 g). ¹H NMR δ (CDCl₃): −0.17 (d, 6H),0.00 (s, 6H), 0.65 (s, 9H), 0.76 (s, 9H), 1.08 (d, 3H), 3.50 (m, 2H),4.25 (sextet, 1H), 6.43 (t, 1H), 6.77 (d, 1H), 6.83 (t, 1H), 6.96 (t,1H), 7.06 (d, 1H). m/z 423 (M−H)⁻

3-Hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1,3-thiazol-2-ylbenzamide

Iodo(trimethyl)silane (7.19 mL, 50.5 mmol) was added dropwise to asolution of3-hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-1,3-thiazol-2-ylbenzamide(3.116 g, 10.1 mmol) in acetonitrile (60 mL) under an inert atmosphereand the reaction stirred at RT overnight. Methanol (5 mL) was added andthe reaction stirred a further 10 minutes. Saturated sodium thiosulphatesolution (5 mL) and saturated potassium carbonate solution (5 mL) wereadded and the reaction stirred a further 10 minutes. The organicsolvents were removed in vacuo and the resulting solution partitionedextracted with ethyl acetate (100 mL). The Aqueous layer was adjusted topH 5 with the addition of 1M hydrochloric acid and extracted with ethylacetate. The combined organic layers were washed with brine (20 mL),dried (MgSO₄), and evaporated to a residue which was chromatographed onsilica, eluting with ethyl acetate, to give the desired compound (1.541g).

¹H NMR δ (d₆-DMSO): 1.23 (d, 3H), 3.52 (m, 2H), 4.50 (sextet, 1H), 6.55(t, 1H), 7.04 (t, 1H), 7.18 (t, 1H), 7.27 (d, 1H), 7.55 (d, 1H), 12.47(s, 1H). m/z 295 (M+H)⁺

3-Hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-1,3-thiazol-2-ylbenzamide

A solution of3-{[(1S)-2-methoxy-(1-methylethyl)oxy}-5-{[(2-methylphenyl)methyl]oxy}-N-1,3-thiazol-2-ylbenzamide(6.9 g) and thioanisole (10 mL) in trifluoroacetic acid (65 mL) wasstirred at ambient temperature for 16 hours. The trifluoroacetic acidwas removed in vacuo and the residual oil partitioned between ethylacetate (75 mL) and aqueous sodium hydrogen carbonate solution (200 mL).The aqueous layer was separated, extracted with ethyl acetate (2×75 mL),and the combined organic extracts washed with brine, dried (MgSO₄), andevaporated to a residue which was chromatographed on silica with 50%ethyl acetate in isohexane as eluant to give the desired compound (4.6g).

¹H NMR δ (CDCl₃): 1.3 (d, 3H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 4.5-4.6 (m,1H), 6.65 (s, 1H), 6.95 (d, 1H), 7.05 (s, 1H), 7.1 (s, 1H), 7.25 (d,1H). m/z 309 (M+H)⁺

3-{[(1S)-2-Methoxy-(1-methylethyl)oxy}-5-{[(2-methylphenyl)methyl]oxy}-N-1,3-thiazol-2-ylbenzamide

To a solution of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[(2-methylphenyl)methyl]oxy}benzoicacid (9.55 g) in DCM (140 mL) was added oxalyl chloride (2.83 mL),followed by DMF (1 drop), and the mixture stirred at ambient temperaturefor 16 hours. The DCM and excess oxalyl chloride were removed in vacuo,the residual oil dissolved in DCM (25 mL) and added to a solution of2-aminothiazole (2.84 g) and triethylamine (7.88 mL) in DCM (75 mL) at0-5° C., and the mixture stirred at ambient temperature for 4 hours. TheDCM and excess triethylamine were removed in vacuo, the residual oilpartitioned between ethyl acetate (100 mL) and 1M hydrochloric acid (100mL). The ethyl acetate layer was separated, washed sequentially with 1Mhydrochloric acid, aqueous sodium hydrogen carbonate solution, andbrine, dried (MgSO₄), and evaporated to a residue which waschromatographed on alumina with ethyl acetate as eluant to give thedesired compound (11.0 g). ¹H NMR δ (CDCl₃): 1.3 (d, 3H), 2.35 (s, 3H),3.4 (s, 3H), 3.5-3.6 (m, 2H), 4.55-4.6 (m, 1H), 5.0 (s, 2H), 6.8 (s,1H), 6.95 (d, 1H), 7.15 (s, 1H), 7.25 (m, 5H), 7.4 (d, 1H). m/z 413(M+H)⁺

3-[(1S)-2-Methoxy-(1-methylethyl)oxy]-5-{[(2-methylphenyl)methyl]oxy}benzoicacid

A solution of methyl3-[{(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[(2-methylphenyl)methyl]oxy}benzoate(10.65 g) in THF (200 mL) and methanol (50 mL) was added to a solutionof lithium hydroxide monohydrate (6.0 g) in water (100 mL). The mixturewas stirred at ambient temperature for 16 hours and the THF and methanolremoved in vacuo. The aqueous layer was acidified to pH1 withhydrochloric acid, and extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were washed with brine, dried (MgSO₄), andevaporated to give the desired compound (9.55 g). m/z 329 (M−H)⁻

Methyl3-[{(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[(2-methylphenyl)methyl]oxy}benzoate

A stirred suspension of methyl3-hydroxy-5-{[(2-methylphenyl)methyl]oxy}benzoate (15.3 g) andpolymer-supported triphenyl phosphine (39.2 g) in dry DCM (900 mL) wascooled in an ice-bath and diisopropyl azodicarboxylate (11.88 mL) wasadded drop wise. The reaction mixture was stirred at 0-5° C. for 30minutes and (R)-1-methoxy-propan-2-ol was added dropwise. The reactionmixture was stirred at ambient temperature for 16 hours, filteredthrough diatomaceous earth and the DCM evaporated to a residue which waschromatographed on silica with 10% ethyl acetate in isohexane as eluantto give the desired compound (10.7 g). ¹H NMR δ (CDCl₃): 1.3 (d, 3H),2.4 (s, 3H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 3.9 (s, 3H), 4.55-4.6 (m,1H), 5.0 (s, 2H), 6.8 (s, 1H), 7.25 (m, 5H), 7.4 (d, 1H)

Methyl 3-hydroxy-5-{[(2-methylphenyl)methyl]oxy}benzoate

To a solution of methyl 3,5-dihydroxybenzoate (50 g, 0.30 mol) in DMF(500 mL) at 0° C. was added sodium hydride (10.8 g, 0.27 mol)portionwise, maintaining the reaction temperature below 10° C. Thereaction was allowed to warm to 15° C., and was stirred for 20 minutes.The mixture was cooled to 0° C. and a solution of 2-methylbenzyl bromide(36 mL, 0.27 mol) in DMF (50 mL) was added over 30 minutes. The reactionwas warmed to ambient temperature and concentrated in vacuo, theresidual oil partitioned between ethyl acetate (500 mL) and water (250mL), the ethyl acetate layer separated, washed sequentially with waterand brine, dried (MgSO₄) and evaporated to a residue which waschromatographed on silica eluting with a gradient of 0-100% ethylacetate in isohexane to give the desired compound (21.9 g). ¹H NMR δ(CDCl₃) 2.39 (s, 3H), 3.90 (s, 3H), 5.02 (s, 2H), 5.61 (s, 1H), 6.69 (t,1H), 7.15-7.42 (m, 6H).

The preparation of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[((1S)-1-methyl-2-{[tris(1-methylethyl)silyl]oxy}ethyl)oxy]benzamideused in the synthesis of Example 1c-1d is described below:

3-Hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[((1S)-1-methyl-2-{[tris(1-methylethyl)silyl]oxy}ethyl)oxy]benzamide

10% Palladium on carbon was added to3-(benzyloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide(21.7 g, 40.4 mmol) in dry THF (480 mL) under argon. The reactionmixture was degassed and placed under a hydrogen balloon and stirred for16 hours. The atmosphere was replaced with argon and mixture wasfiltered through diatomaceous earth then the filtrate evaporated anddried under high vacuum for 1 hour to give the title compound (18.2 g).¹H NMR δ (CDCl₃): 1.05 (s, 18H), 1.05-1.1 (m, 3H), 1.3 (d, 3H), 3.7 (m,1H), 3.8 (s, 3H), 3.9 (m, 1H), 4.5 (m, 1H), 6.6 (s, 1H), 6.8 (s, 1H),7.0 (m, 2H), 7.20 (s, 1H), 7.3 (s, 1H), 8.7 (s, 1H). m/z 448 (M+H)⁺, 446(M−H)-3-(Benzyloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide

HATU (23.5 g, 61.8 mmol) was added to3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoicacid (23.6 g, 51.5 mmol), followed by addition of DMF (140 mL), andcooled to 0° C. 3-Amino-1-methylpyrazole (6.00 g. 61.8 mmol) was addedfollowed by DIPEA (21.3 mL) and the reaction was stirred under argon at0° C. for 3 hours. The solvent was evaporated and the residue wasdissolved in ethyl acetate (500 mL) and washed with citric acid solution(200 mL), sodium hydrogen carbonate solution (150 mL), and saturatedbrine solution (2×150 mL). The organic layer was separated and dried(MgSO₄), filtered and evaporated. Purification by column chromatography,eluting with 1:4 to 1:1 ethyl acetate:hexanes, afforded the titlecompound as a colourless oil (21.7 g).

¹H NMR δ (CDCl₃): 1.05 (s, 18H), 1.05-1.1 (m, 3H), 1.3 (d, 3H), 3.7 (m,1H), 3.8 (s, 3H), 3.9 (m, 1H), 4.5 (m, 1H), 5.1 (s, 2H), 6.7 (s, 1H),6.8 (s, 1H), 7.0 (m, 2H), 7.1 (s, 1H), 7.3 (s, 1H), 7.35-7.5 (m, 5H),8.5 (s, 1H). m/z 538 (M+H)⁺

3-(Benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoicacid

Lithium hydroxide monohydrate (12.14 g, 0.289 mol) in water (100 mL) wasadded to a solution of methyl3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoate(62 g, 0.131 mol) in THF (300 mL) and warmed to 43° C. The reaction wasstirred for 16 hours, the THF removed in vacuo and the resultant mixtureacidified to pH 5 with 10% w/v citric acid. This was extracted withethyl acetate (2×300 mL) and the combined organic layers were dried(MgSO₄), filtered and evaporated to afford the title compound (60.2 g).

¹H NMR δ (CDCl₃): 1.05 (s, 18H), 1.05-1.1 (m, 3H), 1.35 (d, 3H), 3.7 (m,1H), 3.9 (m, 1H), 4.5 (m, 1H), 5.1 (s, 2H), 6.8 (s, 1H), 7.3-7.5 (m,7H). m/z 457 (M−H)⁻

Methyl3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoate

(2R)-1-[(Triisopropylsilyl)oxy]propan-2-ol (56.1 g, 242 mmol) was addedto a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (50 g,194 mmol) and triphenylphosphine (63.5 g, 242 mmol) in dry THF (500 mL),at to 0° C., followed by addition of DIAD (47.6 mL, 242 mmol) over 45minutes under an argon atmosphere. The reaction was stirred at 0° C. for1 hour and allowed to warm up to RT over an hour then stirred at RT for1 hour. The THF was evaporated and a mixture of ethyl acetate (80 mL)and hexane (120 mL) was added. This mixture stirred for 2 hours andfiltered. The precipitate was washed with a mixture of ethyl acetate (20mL) and hexane (180 mL) and the filtrate evaporated. The residue waspurified by column chromatography, eluting with 1:20 to 1:10 ethylacetate:hexanes, to afford the title compound (65.5 g).

¹H NMR δ (CDCl₃): 1.05 (s, 18H), 1.05-1.1 (m, 3H), 1.35 (d, 3H), 3.7 (m,1H), 3.9 (m, 1H), 3.9 (s, 3H), 4.5 (m, 1H), 5.05 (s, 2H), 6.75 (s, 1H),7.2 (s, 1H). 7.3-7.5 (m, 6H). m/z 471 (M−H)⁻

(2R)-1-[(Triisopropylsilyl)oxy]propan-2-ol

Triisopropylsilyl chloride (83.8 mL, 390 mmol) was added slowly over 15minutes to a solution of (2R)-propane-1,2-diol (29.7 g, 390 mmol) in DMFat 0° C. (100 mL) keeping the internal temperature below 15° C. This wasfollowed by addition of imidazole (66.4 g, 975 mmol) and the reactionmixture was allowed to warm to RT and stirred under argon for 20 hours.The reaction was quenched with 1M hydrochloric acid/diethyl ether (300mL/800 mL). The organic layer was separated and washed with 1Mhydrochloric acid followed by saturated brine solution. The organiclayer was dried (MgSO₄), filtered and evaporated. Purification bydistillation at 10 mmHg, 90-104° C., afforded the title compound ascolourless oil (69.5 g). ¹H NMR δ (CDCl₃): 1.05 (s, 18H), 1.05-1.1 (m,3H), 1.05 (d, 3H), 2.55 (s, 1H), 3.45 (dd, 1H), 3.7 (dd, 1H), 3.85 (m,1H).

Methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate

To a stirred solution of methyl 3,5-dihydroxybenzoate (5.95 mol) in DMF(6 L) was added potassium carbonate (9 mol), and the suspension stirredat ambient temperature under argon. To this was added benzyl bromide(8.42 mol) slowly over 1 hour, with a slight exotherm, and the reactionmixture stirred overnight at ambient temperature. The reaction wasquenched cautiously with ammonium chloride solution (5 L) followed bywater (35 L). The aqueous suspension was extracted with DCM (1×3 L and2×5 L). The combined extracts were washed with water (10 L) and driedovernight (MgSO₄). The solution was evaporated in vacuo, and the crudeproduct chromatographed in 3 batches (flash column, 3×2 kg silica,eluting with a gradient consisting of hexane containing 10% DCM, to neatDCM, to DCM containing 50% ethyl acetate) to eliminate startingmaterial. The crude eluant was further chromatographed in 175 g batches(Amicon HPLC, 5 kg normal-phase silica, eluting with isohexanecontaining 20% v/v of ethyl acetate) to give the desired compound (21%yield). ¹H NMR δ (d₆-DMSO): 3.8 (s, 3H), 5.1 (s, 2H), 6.65 (m, 1H), 7.0(m, 1H), 7.05 (m, 1H), 7.3-7.5 (m, 5H), 9.85 (br s, 1H).

EXAMPLE 23-{[5-(Azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Potassium carbonate (0.181 g, 1.31 mmol) was added to a mixture of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide(0.2 g, 0.66 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (129mg, 0.66 mmol) in acetonitrile (5.0 mL) and the stirred mixture heatedat 160° C. in a ‘Biotage initiator Microwave’ for 6 hours. The mixturewas allowed to reach RT and pressure and was partitioned between ethylacetate (50 mL) and water (50 mL). The ethyl acetate layer wasseparated, washed with water (5×50 mL) brine (50 mL), dried (MgSO₄) andevaporated to a residue which was chromatographed on silica, elutingwith a gradient of 0-5% methanol in ethyl acetate, to give the desiredcompound (202 mg). ¹H NMR δ (CDCl₃): 1.33 (d, 3H), 2.38 (quin, 2H), 3.40(s, 3H), 3.61-3.47 (m, 2H), 3.74 (s, 3H), 4.42-4.18 (m, 4H), 4.58(sextet, 1H), 6.80 (d, 1H), 6.91 (t, 1H), 6.97 (d, 1H), 7.21 (t, 1H),7.26 (d, 1H), 7.33 (t, 1H), 8.09-8.05 (m, 1H), 8.42 (d, 1H), 8.92 (s,1H); m/z 466 (M+H)⁺

In a similar manner, Examples 2a-2g were prepared using the appropriatephenol and halopyridine:

Example Structure m/z NMR 2a

500(M + H)⁺ ¹H NMR δ (CDCl₃): 1.31 (d, 3H), 2.36(quintet, 2H), 3.38 (s,3H), 3.59-3.45 (m,2H), 3.67 (s, 3H), 4.39-4.15 (m, 4H), 4.55(sextet,1H), 6.79 (d, 1H), 6.92 (t, 1H), 7.20(t, 1H), 7.25 (d, 1H), 7.35 (t,1H), 8.14 (d,1H), 8.20 (d, 1H), 9.42 (s, 1H) 2b

439(M + H)⁺ ¹H NMR δ (CDCl₃): 1.36 (d, 6H), 2.39 (m,2H), 4.42-4.19 (m,4H), 4.58 (septet, 1H),6.90 (d, 1H), 6.93 (t, 1H), 6.98 (d, 1H), 7.22(d,1H), 7.34 (t, 1H), 7.40 (m, 1H), 8.08 (m,1H), 8.41 (d, 1H), 12.21 (s,1H) 2c

473(M + H)⁺ ¹H NMR δ (CDCl₃): 1.37 (d, 6H), 2.39(quintet, 2H), 4.39-4.20(m, 4H), 4.59(septet, 1H), 6.92 (d, 1H), 6.96 (t, 1H), 7.23(d, 1H), 7.36(t, 1H), 7.44 (t, 1H), 8.16 (d,1H), 8.23 (d, 1H), 12.37 (s, 1H) 2d

436(M + H)⁺ ¹H NMR δ (CDCl₃): 1.32 (d, 6H), 2.34(quintet, 2H), 3.71 (s,3H), 4.37-4.17 (m,4H), 4.54 (septet, 1H), 6.77 (d, 1H), 6.82 (t,1H) 6.94(d, 1H), 7.15 (t, 1H), 7.23 (d, 1H),7.25 (m, 1H), 8.04 (m, 1H), 8.38 (d,1H),8.85 (s, 1H) 2e

470(M + H)⁺ ¹H NMR δ (CDCl₃): 1.37 (d, 6H), 2.40(quintet, 2H), 3.78 (s,3H), 4.41-4.20 (m,4H), 4.61 (septet, 1H), 6.81 (d, 1H), 6.89 (t,1H),7.20 (t, 1H), 7.29 (m, 1H), 7.32 (t, 1H),8.17 (d, 1H), 8.25 (d, 1H),8.72 (s, 1H) 2f

484(M + H)⁺ ¹H NMR δ (CDCl₃): 1.34 (d, 3H), 2.39(quintet, 2H), 2.47 (s,3H), 3.41 (s, 3H), 3.63-3.49 (m, 2H), 4.43-4.20 (m, 4H), 4.61(sextet,1H), 7.00 (m, 2H), 7.37 (t, 1H), 7.44(t, 1H), 8.40 (d, 1H), 11.08 (s,1H) 2g

518(M + H)⁺ ¹H NMR δ (CDCl₃): 1.34 (d, 3H), 2.40(quintet, 2H), 2.44 (s,3H), 3.41 (s, 3H), 3.64-3.49 (m, 2H), 4.45-4.20 (m, 4H), 4.61(sextet,1H), 7.04 (t, 1H), 7.40 (t, 1H), 7.42(s, 1H), 8.17 (d, 1H), 8.21 (d,1H), 11.32 (s, 1H)

The preparation of the halopyridines is described in Example 1.

The preparation of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamideused in the synthesis of Examples 2 and 2a is described below:

3-Hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide

To a solution of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(7.07 g) in THF (50 mL) and methanol (50 mL) was added 10% palladium oncarbon (727 mg) as a slurry in THF (1 mL) and methanol (1 mL). Themixture was placed under vacuum and stirred under an atmosphere ofhydrogen for 70 hours. The mixture was filtered through diatomaceousearth, and the diatomaceous earth washed with methanol (2×100 mL),followed by evaporation in vacuo. The residues were dissolved in ethylacetate (10 mL), treated with isohexane (40 mL), the solid filtered offand washed with isohexane (50 mL) to afford the desired compound (5.17g) which was used without further purification.

¹H NMR δ (d₆-DMSO): 1.22 (d, 3H), 3.28 (s, 3H, obscured by water),3.38-3.53 (m, 2H), 3.76 (s, 3H), 4.65 (m, 1H), 6.44 (m, 1H), 6.54 (m,1H), 6.93 (s, 1H), 7.04 (s, 1H), 7.57 (m, 1H), 9.63 (br s, 1H), 10.60(s, 1H). m/z 306 (M+H)⁺, 304 (M−H)⁻

3-[(1S)-2-Methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide

A solution of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid(8.73 g) in DCM (150 mL) was cooled to 0° C. Oxalyl chloride (4.81 mL)and DMF (0.15 mL) were slowly added with stirring. The mixture wasallowed to warm to ambient temperature and stirred for 16 hours,following which the organics were removed in vacuo, and the residuesazeotroped with toluene (75 mL). The crude material was dissolved in DCM(75 mL) and slowly added to a stirred suspension of3-amino-1-methylpyrazole (3.35 g) and DIPEA (14.4 mL) in DCM (75 mL).The mixture was stirred at ambient temperature for 18 hours, before theorganics were evaporated in vacuo and the residue dissolved in ethylacetate (150 mL). The organics were washed with 1M aqueous hydrochloricacid (100 mL) and brine (50 mL), and dried (MgSO₄), before evaporationin vacuo to give crude material. This was chromatographed on a 200 gBiotage Flash 75 SiO₂ column (eluting with 30 to 90% ethyl acetate inisohexane), and evaporated in vacuo to afford the desired compound (7.07g).

¹H NMR δ (d₆-DMSO): 1.23 (d, 3H), 3.28 (s, 3H, obscured by water),3.40-3.52 (m, 2H), 3.77 (s, 3H), 4.70 (m, 1H), 5.03 (s, 2H), 6.56 (m,1H), 6.71 (m, 1H), 7.18 (s, 1H), 7.24 (s, 1H), 7.32-7.47 (br m, 5H),7.58 (m, 1H), 10.73 (s, 1H). m/z 396 (M+H)⁺.

3-[(1S)-2-Methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid

A solution of methyl3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoate(77.4 mmol) in a mixture of THF (232 mL) and methanol (232 mL) wastreated with a solution of 2M sodium hydroxide (232 mmol), and thereaction mixture stirred for 4 hours at ambient temperature. Theresulting solution was diluted with water (250 mL) and most of theorganic solvent removed in vacuo. The resulting suspension was washedwith diethyl ether (3×200 mL) and the organic washings discarded. Theresulting aqueous solution was acidified to pH4 with 2M hydrochloricacid solution and extracted with ethyl acetate (2×200 mL). The extractswere combined, washed with brine, dried (MgSO₄), and evaporated to givethe desired compound (99% yield).

¹H NMR δ (d₆-DMSO): 1.20 (d, 3H), 3.46 (m, 2H), 4.64 (m, 1H), 5.15 (s,2H), 6.83 (app t, 1H), 7.06 (s, 1H), 7.13 (s, 1H), 7.30-7.49 (m, 5H),12.67 (br s, 1H)

Methyl3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoate

To a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (77.4mmol) in THF was added polymer-supported triphenylphosphine (51.7 g of 3mmol/g loading, 155 mmol) and (R)-(−)-1-methoxy-2-propanol (102 mmol).The stirred solution was blanketed with argon and cooled in an ice bath.A solution of DIAD (116 mmol) was added dropwise by syringe over 10minutes. The solution was stirred for 20 minutes and filtered, washingthe residue with THF (500 mL). The filtrate and washings were combined,and evaporated to give the desired compound which was used withoutfurther purification.

¹H NMR δ (d₆-DMSO): 3.26 (s, 3H), 3.44 (m, 2H), 3.82 (s, 3H), 4.63 (m,1H), 5.14 (s, 2H), 6.85 (s, 1H), 7.05 (s, 1H), 7.11 (s, 1H), 7.30-7.47(m, 5H)

The ¹H NMR spectrum also contained signals consistent with a smallamount of bis(1-methylethyl)hydrazine-1,2-dicarboxylate.

The preparation of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate isdescribed in Example 1c.

The preparation of3-hydroxy-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide used in thepreparation of Examples 2b and 2c is described below:

3-Hydroxy-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide

3-[(1-Methylethyl)oxy]-5-[(phenylmethyl)oxy]-N-1,3-thiazol-2-ylbenzamide(11.2 g) was dissolved in trifluoroacetic acid (60 mL) and treated withthioanisole (17.8 mL). The mixture was left to stir at ambienttemperature for 18 hours before the trifluoroacetic acid was removed invacuo. The residues were treated with isohexane (100 mL) and the solidfiltered off, before being washed with further isohexane (2×20 mL). Thesolid was dissolved in ethyl acetate (200 mL) and washed with aqueoussaturated sodium hydrogen carbonate solution (100 mL). The organics werewashed with water (100 mL) and brine (100 mL), and dried (MgSO₄) beforeevaporation in vacuo to afford a solid which was washed with isohexane(200 mL) and dried in vacuo to give the desired compound (7.18 g). ¹HNMR 8 (d₆-DMSO): 1.27 (d, 6H), 4.55 (m, 1H), 6.49 (m, 1H), 7.02 (s, 1H),7.14 (s, 1H), 7.25 (d, 1H), 7.54 (d, 1H), 9.73 (s, 1H), 12.44 (s, 1H).m/z 279 (M+H)⁺, 277 (M−H)⁻

3-[(1-Methylethyl)oxy]-5-[(phenylmethyl)oxy]-N-1,3-thiazol-2-ylbenzamide

To a solution of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoicacid (20 g) in DCM (400 mL), cooled to 0° C. was slowly added oxalylchloride (12.2 mL) and DMF (0.4 mL), with stirring. The mixture wasallowed to warm to ambient temperature and stirred for a further 16hours, following which the organics were removed in vacuo, and theresidues azeotroped with toluene (100 mL). The crude material wasdissolved in DCM (200 mL) and slowly added to a stirred suspension of2-aminothiazole (10.5 g) and diisopropylethylamine (24.3 mL), in DCM(200 mL). The mixture was stirred at ambient temperature for 70 hours,before the organics were removed in vacuo. The residues were dissolvedin ethyl acetate (300 mL) and washed with 1M aqueous hydrochloric acid(300 mL). The aqueous layer was extracted with further ethyl acetate(300 mL), and the combined organics washed with brine (75 mL), and dried(MgSO₄), before evaporation in vacuo to give the desired compound (28 g)which was used without further purification.

¹H NMR 8 (d₆-DMSO): 1.27 (d, 6H), 4.70 (m, 1H), 5.15 (s, 2H), 6.77 (m,1H), 7.27 (m, 2H), 7.33-7.47 (brm, 6H), 7.55 (d, 1H). m/z 369 (M+H)⁺,367 (M−H)⁻;

The ¹H NMR spectrum also contained signals consistent with a smallamount of ethyl acetate.

3-[(1-Methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid

To a solution of methyl3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoate (37 g) in a 1:1mixture of THF:methanol (300 mL) was added 4M sodium hydroxide solution(150 mL). The mixture was refluxed for 45 minutes, following which theorganics were removed in vacuo. The aqueous was acidified to pH4 withhydrochloric acid (2M), and extracted with ethyl acetate. The organicswere combined, washed with water and brine, dried (MgSO₄) andconcentrated in vacuo to give the desired compound (33.5 g), which wasused without further purification.

¹H NMR 8 (d₆-DMSO): 1.26 (d, 6H), 4.59-4.69 (m, 1H), 5.15 (s, 2H), 6.80(app t, 1H), 7.04 (m, 1H), 7.12 (m, 1H), 7.33 (app t, 1H), 7.40 (t, 2H),7.46 (d, 2H), 12.95 (s, 1H)

Methyl 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoate

To a solution of methyl 3-hydroxy-5-[(1-methylethyl)oxy]benzoate (25 g)in DMF (250 mL) was added anhydrous potassium carbonate (297 mmol), andbenzyl bromide (143 mmol). The mixture was stirred at 60° C. for 5hours, then cooled to room temperature. The solvent was removed in vacuoand the residue partitioned between ethyl acetate and water. Theorganics were combined and washed with further water, brine, dried(MgSO₄) and concentrated in vacuo to give the desired compound (37 g)which was used without further purification.

¹H NMR 8 (d₆-DMSO): 1.26 (d, 6H), 3.84 (s, 3H), 4.61-4.70 (m, 1H), 5.12(s, 2H), 6.84 (t, 1H), 7.05 (app t, 1H), 7.12-7.15 (m, 1H), 7.31-7.37(m, 1H), 7.40 (t, 2H), 7.46 (d, 2H)

Methyl 3-hydroxy-5-[(1-methylethyl)oxy]benzoate

To a stirred solution of methyl 3,5-dihydroxybenzoate (0.1 mol) in DMF(180 mL) was added powdered potassium carbonate (0.2 mol) and2-iodopropane (0.1 mol), and the resulting mixture stirred at ambienttemperature for 16 hours. The reaction mixture was poured into water(1000 mL) and the mixture extracted with ether. The extracts werecombined and washed sequentially with water (twice) and brine; thesolution was dried (MgSO₄), filtered and evaporated in vacuo to give thecrude product as a pale yellow oil (12.6 g). This was treated withtoluene (40 mL) and allowed to stand overnight. The insoluble material(starting phenol) was removed by filtration, and the filtrate evaporatedin vacuo. The resulting oil was chromatographed (2×90 g Biotage silicacartridges), eluting with hexane containing ethyl acetate (10%increasing to 15% v/v). The title compound was obtained as an oil (25%yield), which was identical by tlc to a sample prepared by a similarprocedure. ¹H NMR δ (d₆-DMSO): 1.2 (d, 6H), 3.8 (s, 3H), 4.5-4.6 (hept,1H), 6.55 (m, 1H), 7.85 (m, 1H), 7.95 (m, 1H), 9.8 (s, 1H)

The preparation of3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamideused in Example 2d and 2e is described below:

3-Hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide

3-[(1-Methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(51 g; 0.14 mol) was dissolved in methanol (500 mL) and THF (500 mL) andthe flask evacuated and purged with argon (3 times). 10% Palladium oncarbon (5.1 g) was added and the flask further evacuated and finallypurged with hydrogen gas. The reaction mixture was stirred at ambienttemperature for 20 hours. The reaction mixture was evacuated and purgedwith nitrogen (3 times). The catalyst was filtered off through celite,and the filtrate concentrated in vacuo. Ethyl acetate was added andfiltered to give the desired compound. (30.5 g). A second crop ofmaterial was obtained in the same way (4.0 g).

¹H NMR 8 (d₆-DMSO): 1.30 (d, 6H), 3.78 (s, 3H), 4.68 (sept, 1H), 6.47(m, 1H), 6.60 (s, 1H), 6.94 (s, 1H), 7.05 (s, 1H), 7.60 (s, 1H), 10.63(s, 1H). m/z 276 (M+H)⁺

3-[(1-Methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide

DMF (2 drops) was added to a solution of3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (40.0 g, 0.14mol) and oxalyl chloride (14.6 mL, 0.17 mol) in DCM (700 mL) The mixturewas stirred at ambient temperature for 4 hours and the DCM and excessoxalyl chloride evaporated in vacuo. The residual acid chloride wasdissolved in DCM (300 mL) and added dropwise to 1-methyl-3-aminopyrazole(14.25 g, 0.147 mol) and triethylamine (41 mL, 0.29 mmol) in DCM (300mL), at 0° C. Stirred at ambient temperature for 24 hours. The DCM wasevaporated in vacuo, and the residue partitioned between ethyl acetate(400 mL) and 1N hydrochloric acid (200 mL). The ethyl acetate layer waswashed sequentially with saturated aqueous sodium hydrogen carbonate(200 mL) and brine (100 mL), dried (MgSO₄) and evaporated in vacuo. Theresidue was chromatographed on silica, eluting with a gradient of 50%ethyl acetate in isohexane, to give the desired compound (51 g). ¹H NMRδ (CDCl₃): 1.30 (d, 6H), 3.61 (s, 3H), 4.50 (sept, 1H), 5.01 (s, 2H),6.66 (m, 1H), 6.88 (m, 1H), 7.00 (m, 1H), 7.06 (m, 1H), 7.24 (m, 1H),7.39 (m, 5H), 9.50 (s, 1H). m/z 366 (M+H)⁺

The preparation of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoicacid was described above.

The preparation of3-hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-(3-methyl-1,2,4-thiadiazol-2-yl)benzamideused in Examples 2f and 2 g is described below:

3-Hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-(3-methyl-1,2,4-thiadiazol-2-yl)benzamide

A solution of3-{[(1S)-2-methoxy-(1-methylethyl)oxy}-5-{phenylmethyloxy}-N-(3-methyl-1,2,4-thiadiazol-2-yl)benzamide(9.53 g) and thioanisole (13.9 mL) in trifluoroacetic acid (45 mL) wasstirred at ambient temperature for 16 hours. The trifluoroacetic acidwas removed in vacuo and the residual oil partitioned between ethylacetate (100 mL) and aqueous sodium hydrogen carbonate solution (300mL). The aqueous layer was separated, extracted with ethyl acetate(2×100 mL), and the combined organic extracts washed with brine, dried(MgSO₄), and evaporated to a residue which was chromatographed on silicawith 50% ethyl acetate in isohexane as eluant to give the desiredcompound (4.5 g).

¹H NMR δ (CDCl₃): 1.2 (d, 3H), 2.5 (s, 3H), 3.3 (s, 3H), 3.4-3.6 (m,2H), 4.6-4.7 (m, 1H), 6.6 (s, 1H), 7.05 (s, 1H), 7.1 (s, 1H), 9.85 (s,1H), 13.2 (s, 1H). m/z 324 (M+H)⁺

3-{[(1S)-2-Methoxy-(1-methylethyl)oxy}-5-{phenylmethyloxy}-N-(3-methyl-1,2,4-thiadiazol-2-yl)benzamide

To a solution of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid(15.8 g) in DCM (260 mL) was added oxalyl chloride (5.24 mL), followedby DMF (1 drop), and the mixture stirred at ambient temperature for 16hours. The DCM and excess oxalyl chloride were removed in vacuo, theresidual oil dissolved in DCM (50 mL) and added to a solution of5-amino-3-methyl-1,2,4 thiadiazole (6.05 g) and triethylamine (14.6 mL)in DCM (150 mL) at 0-5° C., and the mixture stirred at ambienttemperature for 16 hours. The DCM and excess triethylamine were removedin vacuo, and the residual oil partitioned between ethyl acetate (250mL) and 1M hydrochloric acid (150 mL). The ethyl acetate layer wasseparated, washed sequentially with 1M hydrochloric acid, aqueous sodiumhydrogen carbonate solution, and brine, dried (MgSO₄), and evaporated toa residue which was chromatographed on alumina with ethyl acetate aseluant, then on silica with 30% ethyl acetate in isohexane as eluant togive the desired compound (9.6 g).

¹H NMR δ (CDCl₃): 1.3 (d, 3H), 2.45 (s, 3H), 3.4 (s, 3H), 3.5-3.6 (m,2H), 4.55-4.6 (m, 1H), 5.05 (s, 2H), 6.8 (s, 1H), 7.1 (m, 2H), 7.25 (m,5H), 10.7 (s, 1H). m/z 414 (M+H)⁺

The synthesis of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acidis described above.

EXAMPLE 33-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A mixture of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide(0.2 g, 0.66 mmol), 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (158 mg,0.66 mmol), cesium carbonate (640 mg, 1.97 mmol) andbromotris(triphenylphosphine)copper(I) (62 mg, 0.07 mmol) in DMA (5 mL)was stirred in a ‘Biotage initiator Microwave’ for 3 hours. The mixturewas allowed to reach RT and pressure and was partitioned between ethylacetate (50 mL) and water (50 mL). The ethyl acetate layer wasseparated, washed with water (5×50 mL), brine (50 mL), dried (MgSO₄) andevaporated to a residue which was chromatographed on silica, elutingwith a gradient of 0-5% methanol in ethyl acetate, to give the desiredcompound (113 mg). The compound was partially crystallised frommethanol. The material was also partially crystallised from isopropylalcohol/isohexane or ethyl acetate/isohexane. Mpt (melting onset) 132.7°C.

¹H NMR δ (CDCl₃): 1.32 (d, 3H), 2.36 (quin, 2H), 3.40 (s, 3H), 3.61-3.47(m, 2H), 3.78 (s, 3H), 4.25 (t, 2H), 4.58 (sextet, 1H), 4.72 (t, 2H),6.80 (t, 2H), 7.11 (s, 1H), 7.31-7.27 (m, 2H), 7.40-7.35 (m, 1H), 8.12(d, 1H), 8.32 (s, 1H), 8.32 (s, 1H). m/z 466 (M+H)⁺

The following compounds were synthesised in an analogous fashion fromthe appropriate phenol and bromopyridine:

Example Structure m/z NMR 3a

466(M + H)⁺ ¹H NMR δ (CDCl₃): 1.34 (d, 3H), 2.40(quintet, 2H), 3.41 (s,3H), 3.49-3.62 (m,2H), 3.80 (s, 3H), 4.25 (t, 2H), 4.37 (t, 2H),4.60(sextet, 1H), 6.80 (m, 2H), 7.10 (t, 1H),7.27 (t, 1H), 7.30 (d, 1H),7.62 (t, 1H), 8.51(d, 1H), 8.61 (s, 2H) 3b

436(M + H)⁺ ¹H NMR δ (CDCl₃): 1.37 (d, 6H), 2.40(quintet, 2H), 3.80 (s,3H), 4.25 (t, 2H), 4.37(t, 2H), 4.60 (septet, 1H), 6.74 (t, 1H), 6.80(s,1H), 7.07 (s, 1H), 7.07 (s, 1H), 7.30 (d,1H), 7.62 (t, 1H), 8.51 (s,1H), 8.61 (s, 2H) 3c

439(M + H)⁺ ¹H NMR δ (CDCl₃): 1.35 (d, 6H), 2.38(quintet, 2H), 4.25 (t,2H), 4.58 (septet, 1H),4.73 (t, 2H), 6.80 (s, 1H), 6.98 (d, 1H), 7.20(d,1H), 7.25 (d, 111), 7.35 (m, 2H), 8.13 (d,1H), 8.31 (d, 1H), 12.15 (s,1H) 3d

436(M + H)⁺ ¹H NMR δ (CDCl₃): 1.28 (d, 6H), 2.26(quintet, 2H), 3.69 (s,3H), 4.18 (t, 2H), 4.49(septet, 1H), 4.63 (t, 2H), 6.65 (s, 1H), 6.72(s,1H), 7.00 (s, 1H), 7.15 (m, 1H), 7.20 (m,2H), 7.28 (m, 1H), 8.02 (d,1H), 8.21 (d, 1H),8.63 (s, 1H) 3e

469(M + H)⁺ ¹H NMR δ (CDCl₃): 1.33 (d, 6H), 2.36(quintet, 2H), 3.38 (s,3H), 3.48-3.60 (m,2H), 4.25 (t, 2H), 4.59 (sextet, 1H), 4.72 (t,2H),6.88 (m, 1H), 6.97 (d, 1H), 7.19 (d, 1H),7.28 (m, 2H), 7.38 (m, 2H),8.12 (d, 1H),8.30 (d, 1H), 12.30 (s, 1H) 3f

484(M + H)⁺ ¹H NMR δ (CDCl₃): 1.27 (d, 3H), 2.29(quintet, 2H), 2.44 (s,3H), 3.31 (s, 3H), 3.4-3.52 (m, 2H), 4.15 (m, 2H), 4.55 (sextet,1H),4.65 (t, 1H), 6.80 (m, 1H), 7.25 (m, 2H), 7.40(m, 1H), 7.60 (m, 1H),8.00 (d, 1H), 8.21 (s, 1H) 3g

454(M + H)⁺ ¹H NMR δ (CDCl₃): 1.30 (d, 6H), 2.29(quintet, 2H), 2.44 (s,3H), 4.18 (m, 2H),4.55 (septet, 1H), 4.65 (t, 1H), 6.74 (m, 1H),7.18 (m,1H), 7.30 (m, 1H), 7.40 (m, 1H),8.00 (d, 1H), 8.23 (s, 1H), 10.05 (s,1H)

The preparation of the required bromopyridines is described earlier.

The preparation of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide,3-hydroxy-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide,3-hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-1,3-thiazol-2-ylbenzamideand3-hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-(3-methyl-1,2,4-thiadiazol-2-yl)benzamideis described earlier.

The preparation of3-hydroxy-5-[(1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamideused in Example 3 g is described below:

3-Hydroxy-5-[(1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide

A solution of3-[(1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)-5-[(phenylmethyl)oxy]benzamide(33 g, 86 mmol), trifluoroacetic acid (160 mL) and thioanisole (50.5 mL)was stirred at ambient temperature for 48 hours. The TFA was removed invacuo and the residue poured into saturated sodium bicarbonate solution(300 mL) and extracted into ethyl acetate (twice). The combined organicextracts were washed with brine, dried (MgSO₄), filtered and the solventremoved in vacuo. The residue was triturated with DCM and washed with 5%ethyl acetate in isohexane to give the desired compound (12.8 g). ¹H NMRδ (d₆-DMSO): 1.31 (d, 6H), 2.51 (s, 3H), 4.67 (sept, 1H), 6.58 (s, 1H),7.08 (s, 1H), 7.24 (s, 1H), 9.88 (s, 1H), 13.25 (brs, 1H). m/z 294(M+H)⁺

3-[(1-Methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)-5-[(phenylmethyl)oxy]benzamide

DMF (2 drops) was added to a solution of3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (29.6 g, 0.103mol) and oxalyl chloride (10.78 mL, 0.12 mol) in DCM (500 mL) Themixture was stirred at ambient temperature for 4 hours and the DCM andexcess oxalyl chloride removed in vacuo. The residual acid chloride wasdissolved in DCM (220 mL) and added dropwise to5-amino-3-methyl-1,2,4-thiadiazole (12.43 g, 0.108 mol) andtriethylamine (30.34 mL, 0.216 mol) in DCM (220 mL), at 0° C. Thereaction was allowed to warm and stirred at ambient temperature for 72hours. The DCM was removed in vacuo, and the residue partitioned betweenethyl acetate (400 mL) and 1N hydrochloric acid (200 mL). The ethylacetate layer was washed sequentially with saturated aqueous sodiumhydrogen carbonate (200 mL) and brine (100 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed on silica,eluting with a gradient of 20% ethyl acetate in isohexane, to give thedesired compound (33 g).

¹H NMR δ (CDCl₃): 1.32 (d, 6H), 2.31 (s, 3H), 4.51 (sept, 1H), 5.05 (s,2H), 6.74 (m, 1H), 7.03 (m, 1H), 7.10 (m, 1H), 7.38 (m, 5H), 11.48 (brs,1H). m/z 384 (M+H)⁺

The preparation of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoicacid is described above.

EXAMPLE 43-{[5-(Azetidin-1-ylsulfonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Triethylamine (0.025 mL, 0.18 mmol) then triethylsilane (0.96 mL, 6.03mmol) were added to palladium (II)acetate (12 mg) in DCM (2 mL) andstirred under argon for 15 mins.3-{[5-(Azetidin-1-ylsulfonyl)-3-bromopyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(0.175 g, 0.3 mmol) in DCM (2 mL) was added dropwise and the reactionstirred at RT for 24 hours. Methanol was added, the reaction filteredthrough celite and the solvent removed in vacuo. Ethyl acetate (30 mL)was added and the mixture washed with water (30 mL), citric acid (30mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed invacuo to give a white solid. This was chromatographed on silica, elutingwith a gradient of 0-100% ethyl acetate in isohexane, to give thedesired compound (69 mg).

¹H NMR δ (CDCl₃): 1.26 (d, 3H), 2.09 (quin, 2H), 3.33 (s, 3H), 3.41-3.55(m, 2H), 3.69 (s, 3H), 3.76 (t, 4H), 4.52 (sextet, 1H), 6.73 (d, 1H),6.87 (t, 1H), 7.02 (d, 1H), 7.17 (t, 1H), 7.20 (m, 1H), 7.28 (s, 1H),8.04 (m, 1H), 8.54 (d, 1H), 8.65 (s, 1H). m/z 502 (M+H)⁺

The preparation of3-{[5-(azetidin-1-ylsulfonyl)-3-bromopyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideis described below:

3-{[5-(Azetidin-1-ylsulfonyl-3-bromopyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-ylbenzamide

A mixture of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide(0.2 g, 0.66 mmol), 5-(azetidin-1-ylsulfonyl)-3-bromo-2-chloropyridine(204 mg, 0.66 mmol) and potassium carbonate (181 mg, 1.31 mmol) inacetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at160° C. for 2 hours. The solvent was removed in vacuo and the residuedissolved in ethyl acetate and water, the organic layer washed withbrine (50 mL), dried (MgSO₄), filtered and the solvent removed in vacuoto give a brown oil which was chromatographed on silica, eluting with agradient of 50-100% ethyl acetate in isohexane, to give the desiredcompound (175 mg).

¹H NMR δ (CDCl₃): 1.26 (d, 3H), 2.12 (quin, 2H), 3.33 (s, 3H), 3.54-3.40(m, 2H), 3.68 (s, 3H), 3.79 (t, 4H), 4.52 (sextet, 1H), 6.73 (d, 1H),6.89 (t, 1H), 7.18 (t, 1H), 7.21 (d, 1H), 7.30 (t, 1H), 8.27 (d, 1H),8.38 (d, 1H), 8.77 (s, 1H). m/z 580, 582 (M+H)⁺

5-(Azetidin-1-ylsulfonyl)-3-bromo-2-chloropyridine

Azetidine hydrochloride (0.32 g, 3.44 mmol) was added to a solution of3-bromo-2-chloropyridine-5-sulfonyl chloride (1 g, 3.44 mmol) in DCM (4mL) and pyridine (10 mL) and stirred at RT for 22 hours. The solvent wasremoved in vacuo and ethyl acetate (30 mL) added. The organic phase waswashed with 1M hydrochloric acid (20 mL), water (20 mL), brine (20 mL),dried (MgSO₄), filtered and the solvent removed in vacuo to give thedesired compound (0.4 g).

¹H NMR δ (CDCl₃): 2.18 (quin, 2H), 3.83 (t, 4H), 8.26 (s, 1H), 8.66 (s,1H).

EXAMPLE 53-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

DIPEA (0.28 mL, 1.59 mmol) was added to a suspension of5-[(3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid (170 mg, 0.4 mmol), HATU (318 mg, 0.84 mmol) and azetidinehydrochloride (75 mg, 0.8 mmol) in DMF (5 mL) and the mixture stirred atRT for 72 hours. Ethyl acetate (40 mL) was added and washed with water(2×30 mL), brine (30 mL), dried (MgSO₄), filtered and reduced in vacuoto give a yellow oil which was chromatographed on silica, eluting with0-100% ethyl acetate in isohexane, to give the desired compound (48 mg).

¹H NMR δ (CDCl₃): 1.26 (d, 3H), 2.31 (quin, 2H), 3.32 (s, 3H), 3.41-3.55(m, 2H), 3.71 (s, 3H), 4.19 (t, 2H), 4.52 (m, 1H), 4.60 (t, 2H), 6.72(s, 1H), 6.86 (m, 1H), 7.16 (m, 1H), 7.20 (m, 1H), 7.28 (m, 1H), 8.25(s, 1H), 8.52 (s, 1H), 8.52 (s, 1H). m/z 467 (M+H)⁺

The preparation of5-[(3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid is described below:

5-[(3-{[(1S)-1-Methyl-2-(methyloxy)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid

A mixture of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide(0.226 g, 0.74 mmol), methyl 5-chloropyrazine-2-carboxylate (192 mg,1.11 mmol) and potassium carbonate (205 mg, 1.48 mmol) in acetonitrile(5 mL) was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 4hours. The solvent was removed in vacuo and water (30 mL) added. Themixture was acidified and extracted into ethyl acetate (3×50 mL), thecombined organics washed with brine (30 mL), dried (MgSO4), filtered andreduced in vacuo to give a brown oil which was a mixture of the acid andmethyl ester. Lithium hydroxide monohydrate (78 mg, 1.85 mmol) in water(2 mL) was added to the mixture of acid and ester (326 mg, 0.74 mmol) inTHF (4 mL) and the mixture stirred at RT for 20 hours. The THF wasremoved in vacuo and the aqueous residue washed with ethyl acetate (20mL) to remove impurities then acidified with 1M citric acid. The productwas extracted into ethyl acetate (2×100 mL) and the combined organicswashed with brine (50 mL), dried (MgSO4), filtered and reduced in vacuoto give a yellow solid (0.17 g). m/z 428 (M+H)⁺

EXAMPLE 63-{[5-(Azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Cesium carbonate (488 mg, 1.5 mmol) was added to a solution of3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide(187 mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole(152 mg, 0.75 mmol) in acetonitrile (5 mL) and the stirred mixtureheated at 160° in a Biotage Initiator Microwave for 2 hours. The mixturewas cooled to RT and pressure, poured onto water (75 mL) then extractedwith ethyl acetate (3×25 mL). The combined organic layers were washedwith brine, dried (MgSO₄) and evaporated to a residue which waschromatographed on silica eluting with ethyl acetate, to give thedesired compound (142 mg). ¹H NMR δ (CDCl₃): 1.3 (d, 6H), 2.4 (m, 2H),3.7 (s, 3H), 4.1-4.4 (m, 4H), 4.5 (m, 1H), 6.75 (s, 1H), 6.9 (s, 1H),7.2 (s, 1H), 7.25 (d, 1H), 7.4 (s, 1H) and 8.95 (s, 1H). m/z 442 (M+H)⁺.

The following example was made in an analogous fashion from5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole and3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide.

Example Structure m/z NMR 6a

472(M + H)⁺ ¹H NMR δ (CDCl₃): 1.3 (d, 3 H), 2.35 (m, 2 H),3.3 (s, 1 H),3.4-3.55 (m, 2 H), 3.7 (s, 3 H), 4.1-4.4 (m, 4 H), 4.5 (m, 1 H), 6.7 (s,1 H), 6.95 (s,1 H), 7.25 (s, 1 H), 7.3 (d, 2 H), 7.4 (s, 1 H) and8.9 (s,1 H).

The preparation of 5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole isdescribed below:

5-(Azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole

To a solution of 2-chlorothiazole-5-carboxylic acid (815 mg, 5 mmol) indichloromethane (10 mL) was slowly added oxalyl chloride (0.53 mL, 6mmol) and then N,N dimethylformamide (1 drop) with stirring. The mixturewas stirred for 16 hours, following which the organics were removed invacuo, and the residues azeotroped with toluene (100 ml). The crudematerial was dissolved in dichloromethane (10 mL) and slowly added to astirred suspension of azetidine hydrochloride (560 mg, 6 mmol) andtriethylamine (2.5 mL, 18 mmol) in dichloromethane (25 mL). The mixturewas stirred at ambient temperature for 2 hours before the organics wereremoved in vacuo. The residue was dissolved in ethyl acetate (50 mL) andwater (25 mL), the organic layer washed with brine (25 mL), dried(MgSO₄) and evaporated to a residue which was chromatographed on silicawith 40% ethyl acetate in iso-hexane as eluant to give5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazoline. ¹H NMR δ (CDCl₃): 2.4(m, 2H), 4.1-4.4 (m, 4H), 4.55 (m, 1H), 7.2 (s, 1H) and 7.75 (s, 1H);m/z 203 (M+H)⁺.

The preparation of3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamideare described earlier.

EXAMPLE 73-{[5-(Azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A solution of6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylicacid (0.20 g, 0.378 mmol), azetidine hydrochloride (0.106 g, 0.114mmol), HATU (0.302 g, 0.794 mmol) and DIPEA (0.39 mL, 0564 mmol) in DMF(7 mL) was stirred at RT overnight. 3.5M Hydrochloric acid (0.5 mL) wasadded and the solution left to stir for 20 minutes. The solution wasneutralised with saturated sodium bicarbonate solution. Water (20 mL)was added and the solution extracted with ethyl acetate (50 mL). Theethyl acetate layer was washed with brine, dried (MgSO₄), and evaporatedto a residue which was chromatographed on silica, eluting with 50% ethylacetate in isohexane, to give the desired product (27 mg). ¹H NMR δ(CDCl₃): 1.32 (d, 3H), 2.38 (quintet, 2H), 3.77 (m, 2H), 3.80 (s, 3H),4.29 (d, 4H), 4.57 (sextet, 1H), 6.81 (d, 1H), 6.91 (t, 1H), 6.99 (d,1H), 7.27 (m, 2H), 7.38 (m, 1H), 8.42 (d, 1H), 8.86 (s, 1H). m/z 452(M+H)⁺

The preparation of6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylicacid is described below:

6-[(3-[((1S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylicacid

A solution of lithium hydroxide monohydrate (0.10 g, 4.17 mmol) in water(15 mL) was added to a solution of methyl6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylate(0.90 g, 1.67 mmol) in THF (30 mL). The mixture was allowed to stir atRT overnight. The THF was removed in vacuo and the resulting solutionwas partitioned between water (50 mL) and ethyl acetate (75 mL), thenthe ethyl acetate layer separated, washed with brine and dried (MgSO₄).The aqueous layer was then taken to pH 7 by addition of 1N hydrochloricacid (5.2 mL) and extracted with ethyl acetate (75 mL). The ethylacetate layer was separated, washed with brine and dried (MgSO₄). Theethyl acetate layers were combined and evaporated to give the requiredproduct (0.84 g).

¹H NMR δ (CDCl₃): 0.05 (d, 6H), 0.88 (s, 9H), 1.36 (d, 3H), 3.70-3.88(m, 5H), 4.52-4.61 (sex, 1H), 6.98 (d, 2H), 7.01 (d, 1H), 6.28 (s, 1H),7.44 (s, 1H), 7.57 (s, 1H), 8.04 (m, 1H), 8.72 (s, 1H), 10.62 (s, 1H).m/z 527 (M+H)⁺

Methyl6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylate

A solution of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide(1.00 g, 2.47 mmol), methyl 6-chloronicotinate (0.450 g, 2.60 mmol), andcesium carbonate (1.204 g, 3.71 mmol) in acetonitrile (15 mL) was heatedat 160° C. using microwave heating for 90 minutes. The acetonitrile wasremoved in vacuo and the residual oil partitioned between water (50 mL)and ethyl acetate (75 mL). The ethyl acetate layer was separated, washedwith brine, dried (MgSO₄), and evaporated to a residue which waschromatographed on silica, eluting with 50% ethyl acetate in isohexane,to give the desired compound (0.977 g).

¹H NMR δ (CDCl₃): 0.05 (d, 6H), 0.87 (s, 9H), 1.34 (d, 3H), 3.54 (m,3H), 3.79 (s, 3H), 3.93 (s, 3H), 4.59 (sextet, 1H), 6.79 (d, 1H), 6.92(t, 1H), 6.96 (s, 1H), 6.99 (s, 1H), 7.20 (t, 1H), 7.27 (d, 1H), 7.33(t, 1H), 8.28 (d, 1H), 8.31 (d, 1H), 8.39 (s, 1H), 8.82 (d, 1H). m/z(M+H)⁺ 541

3-[((1S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide

3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(1.8 g, 3.64 mmol) was dissolved in methanol (50 mL) and the flaskevacuated and purged with nitrogen (3 times). 10% Palladium on carbon(0.2 g) was added and the flask further evacuated and finally purgedwith hydrogen gas. The reaction mixture was stirred at ambienttemperature for 16 hours until completion. The reaction mixture wasevacuated and purged with nitrogen (3 times). The catalyst was filteredoff, and the filtrate concentrated in vacuo to give the desired compound(1.45 g). ¹H NMR δ (d₆-DMSO): 0.02 (d, 6H), 0.83 (s, 9H), 1.18 (d, 3H),3.66 (m, 2H), 3.72 (s, 3H), 4.51 (m, 1H), 6.42 (m, 1H), 6.52 (m, 1H),6.90 (s, 1H), 7.02 (s, 1H), 7.55 (m, 1H), 9.58 (br s, 1H), 10.59 (br s,1H). m/z 406 (M+H)⁺

3-[((1S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide

DIPEA (4.06 g, 23.4 mmol) was added to a suspension of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoicacid (2.43 g, 5.84 mmol), 3-amino-1-methylpyrazole (0.85 g, 8.76 mmol)and HATU (4.66 g, 12.3 mmol) in DMF (50 mL) and stirred at ambienttemperature for 16 hours. The resultant mixture was partially reduced invacuo, poured onto water (100 mL) and extracted with diethyl ether (2×50mL). The extracts were washed with water and brine then dried (MgSO₄),filtered and reduced to an opaque gum which partially crystallized. Thecrude product was purified by column chromatography, eluting with 0-100%ethyl acetate in isohexane, to give the title compound as a colourlessoil (1.87 g).

¹H NMR δ (d₆-DMSO): 0.02 (d, 6H), 0.84 (s, 9H), 1.21 (d, 3H), 3.68 (d,2H), 3.76 (s, 3H), 4.58 (m, 1H), 5.13 (s, 2H), 6.56 (m, 1H), 6.70 (m,1H), 7.18 (s, 1H), 7.24 (s, 1H), 7.29-7.46 (m, 5H), 7.57 (m, 1H), 10.74(br s, 1H). m/z 496 (M+H)⁺

3-[((1S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoicacid

Methyl3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoate(3.0 g, 6.98 mmol) was dissolved in THF (50 mL) and water (10 mL) andlithium hydroxide monohydrate (586 mg, 13.95 mmol) added. The resultantmixture was heated with stirring at 45° C. for 2 hours, then at ambienttemperature for 16 hours, and at 45° C. for a further 4 hours. Water (40mL) was added and the solvent removed in vacuo. The resultant solutionwas acidified carefully with 1M citric acid (2 equivalents), washed withwater and brine then dried (MgSO₄), filtered and evaporated in vacuo togive the title compound as a colourless gum (2.58 g).

¹H NMR δ (d₆-DMSO): 0.02 (d, 6H), 0.84 (s, 9H), 1.17 (d, 3H), 3.66 (m,2H), 4.43 (m, 1H), 5.05 (s, 2H), 6.56 (br s, 1H), 7.10 (br s, 1H), 7.17(br s, 1H), 7.25-7.44 (m, 5H), 7.60 (br s, 1H).

Methyl3-[((1S)-2-{[(1,1-dimethylethyl(di-ethylsilyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoate

(2R)-1-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}propan-2-ol (3.31 g,17.4 mmol) was added to a solution of methyl3-hydroxy-5-{[phenylmethyl]oxy}benzoate (3.00 g, 11.6 mmol) in THF (50mL) at 0° C. followed by addition of triphenylphosphine (4.57 g, 17.4mmol) then DIAD (3.43 mL, 17.4 mmol) and the reaction was warmed to RTand stirred for 16 h. The reaction was quenched with water (100 mL) anddiethyl ether (400 mL) and the organic layer was separated then dried(MgSO₄) and evaporated. Purification by column chromatography, elutingwith 1:15 to 1:5 ethyl acetate:hexane, afforded the title compound as acolourless oil (4.00 g, 80%).

¹H NMR δ (CDCl₃): 0.03 (s, 3H), 0.05 (s, 3H), 0.89 (s, 9H), 1.29 (d,3H), 3.63 (dd, 1H), 3.78 (dd, 1H), 3.92 (s, 3H), 4.44 (m, 1H), 5.08 (s,2H), 6.77 (m, 1H), 7.40 (m, 7H)

The preparation of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate wasdescribed earlier.

(2R)-1-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}propan-2-ol

tert-Butyl(dimethyl)silyl chloride (5.90 g, 39.5 mmol) was added to asolution of (2R)-propane-1,2-diol (3.00 g, 39.5 mmol) in DCM (100 mL)followed by diisopropylethylamine (7.10 g, 55.3 mmol) and the reactionwas stirred under argon for 72 h. The reaction was diluted with diethylether (500 mL) and water (140 mL) and the organic layer was separatedthen dried (MgSO₄), filtered and evaporated. Purification by columnchromatography, eluting with 1:15 to 1:10 ethyl acetate:hexane, affordedthe title compound as a colourless oil (6.00 g, 80%).

¹H NMR δ (CDCl₃): 0.10 (m, 6H), 0.92 (s, 9H), 1.14 (d, 3H), 2.42 (d,1H), 3.38 (dd, 1H), 3.60 (dd, 1H), 3.82 (m, 1H).

The data matched that reported in the literature (J. Org. Chem., 1998,53, 2300).

EXAMPLE 83-{[3-Chloro-5-(morpholin-4-ylcarbonyl)pyridin-2-yl]oxy-}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A solution5-chloro-6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylicacid (0.15 g, 0.267 mmol), morpholine (0.07 mL, 0.803 mmol), HATU (0.213g, 0.560 mmol) and DIPEA (0.15 mL, 0.861 mmol) in DMF (7 mL) was stirredat RT for 2 days. Water (20 mL) was added and the solution extractedwith ethyl acetate (50 mL). The ethyl acetate layer was separated,washed with brine and dried (MgSO₄), and evaporated to a residue whichwas chromatographed on silica, eluting with 1% methanol in ethylacetate. 3.5M Hydrochloric acid (0.5 mL) was added to a solution of theresidual solid taken up in methanol (5 mL) and allowed to stir at RT for20 minutes. The solution was neutralised with saturated sodiumbicarbonate solution and the methanol removed in vacuo and the residualsolution partitioned between water (20 mL) and ethyl acetate. The ethylacetate layer was separated and washed with brine, dried (MgSO₄) andevaporated to give the desired product (34 mg). ¹H NMR δ (d6-DMSO): 1.28(d, 3H), 3.58 (m, 10H), 3.81 (s, 3H), 4.61 (sextet, 1H), 4.89 (t, 1H),6.60 (d, 1H), 7.03 (t, 1H), 7.41 (s, 1H), 7.54 (s, 1H), 7.63 (d, 1H),8.20 (q, 2H), 10.84 (s, 1H). m/z 516 (M+H)⁺

The preparation of5-chloro-6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylicacid is described below:

5-Chloro-6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylicacid

To a solution of methyl5-chloro-6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylate(1.2 g, 2.09 mmol) in THF (50 mL) was added a solution of lithiumhydroxide monohydrate (0.219 g, 5.22 mmol) in water (30 mL). The mixturewas allowed to stir under RT overnight. The THF was removed in vacuo andthe resulting solution was partitioned between water (50 mL) and ethylacetate (75 mL), and the ethyl acetate layer separated, washed withbrine and dried (MgSO₄). The aqueous layer was then adjusted to pH 7 byaddition of 1N hydrochloric acid (5.2 mL) and partitioned between ethylacetate (75 mL). The ethyl acetate layer was separated, washed withbrine and dried (MgSO₄). The ethyl acetate layers were combined andevaporated to give the required product (1.1 g).

¹H NMR δ (d₆-DMSO): 0.01 (d, 6H), 0.82 (s, 9H), 1.22 (d, 3H), 3.73 (m,2H), 3.76 (s, 3H), 4.55 (sextet, 1H), 6.55 (d, 1H), 6.90 (t, 1H), 7.30(s, 1H), 7.44 (s, 1H), 7.58 (d, 1H), 8.36 (d, 1H), 8.19 (d, 1H), 8.51(s, 1H). m/z (M+H)⁺ 562

Methyl5-chloro-6-[(3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyloxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyridine-3-carboxylate

A solution of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide(1.0 g, 2.47 mmol), ethyl 5,6-dichloronicotinate (0.57 g, 2.59 mmol),and potassium carbonate (0.855 g, 6.14 mmol) in acetonitrile (15 mL) washeated at 160° C. for 4 hours using microwave heating. The acetonitrilewas removed in vacuo and the residual oil partitioned between water (50mL) and ethyl acetate (75 mL). The ethyl acetate layer was separated,washed with brine, dried (MgSO₄), and evaporated to a residue which waschromatographed on silica, eluting with 50% ethyl acetate in hexane togive the desired compound (1.1 g). The analytical data indicated thattransesterification had occurred at some stage in the procedure tofurnish the methyl ester.

¹H NMR δ (CDCl₃): 0.05 (d, 6H), 0.87 (s, 9H), 1.30 (d, 3H), 3.72 (s,3H), 3.73 (m, 1H), 3.93 (s, 3H), 4.47 (sextet, 1H), 6.80 (d, 1H), 6.93(t, 1H), 7.19 (t, 1H), 7.25 (d, 1H), 7.26 (s, 1H), 7.34 (t, 1H), 8.35(d, 1H), 8.61 (d, 1H), 8.97 (s, 1H); m/z (M+H)⁺ 575

The preparation of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamideis described earlier.

EXAMPLE 93-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A mixture of3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide(200 mg, 0.64 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (164mg, 0.71 mmol) and potassium carbonate (178 mg, 1.28 mmol) inacetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at120° C. for 4 hours. The solvent was removed in vacuo and the residuepartitioned between ethyl acetate and water (100 mL), the organic layerwashed with brine (50 mL), dried (MgSO₄), filtered and the solventremoved in vacuo to give a brown oil which was chromatographed onsilica, eluting with a gradient of 50-100% ethyl acetate in isohexane,to give the desired compound (237 mg).

¹H NMR δ (CDCl₃): 2.39 (quintet, 2H), 3.74 (s, 3H), 4.25 (t, 2H), 4.37(t, 2H), 4.63 (m, 2H), 4.74 (m, 3H), 6.81 (s, 1H), 7.01 (s, 1H), 7.29(m, 1H), 7.31 (s, 1H), 7.42 (s, 1H), 8.17 (s, 1H), 8.23 (s, 1H), 9.26(s, 1H). m/z 506 (M+H)⁺

The preparation of 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine isdescribed above. The preparation of3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamideis described below:

3-{[2-Fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A solution of3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(2.46 g, 6.13 mmol) and 10% by weight palladium on carbon (0.246 g) inethanol (100 mL) was allowed to stir at RT, under a hydrogen atmosphereovernight. The solution was filtered through Celite® and the cake washedwith methanol (100 mL). The solution was evaporated to give the desiredcompound (1.78 g). ¹H NMR δ (d₆-DMSO): 3.78 (s, 3H), 4.72 (m, 4H), 4.97(m, 1H), 6.57 (d, 2H), 7.03 (s, 1H), 7.16 (s, 1H), 7.59 (s, 1H). m/z 312(M+H)⁺

3-{[2-Fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide

A solution3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoicacid (3.00 g, 9.31 mmol), 3-amino-1-methylpyrazole (1.83 g, 18.6 mmol),HATU (4.60 g, 12.1 mmol) and DIPEA (3.25 mL, 18.6 mmol) in DMF (12 mL)was stirred at RT overnight. Water (150 mL) was added and the solutionpartitioned with ethyl acetate (250 mL). The ethyl acetate layer wasseparated, washed with brine and dried (MgSO₄), and evaporated to aresidue which was chromatographed on silica, eluting with 50% ethylacetate in isohexane, to give the desired product (2.46 g).

¹H NMR δ (CDCl₃): 3.69 (s, 3H), 4.57 (m, 5H), 5.00 (s, 2H), 6.70 (t,1H), 6.74 (d, 1H), 7.01 (t, 1H), 7.08 (t, 1H), 7.21 (d, 1H), 7.30 (m,5H), 8.68 (s, 1H); m/z 402 (M+H)⁺

3-{[2-Fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoicacid

A solution of lithium hydroxide monohydrate (2.32 g, 55.1 mmol) in water(100 mL) was added to a solution of methyl3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoate(7.41 g, 22.0 mmol) in THF (200 mL) and the mixture allowed to stir atRT overnight. The THF was removed in vacuo and the resulting solutionpartitioned between water (100 mL) and ethyl acetate (250 mL). The ethylacetate layer was separated, washed with brine and dried (MgSO₄). Theaqueous layer was then adjusted to pH 7 by addition of 1M hydrochloricacid and extracted with ethyl acetate (75 mL). The ethyl acetate layerwas separated, washed with brine and dried (MgSO₄). The ethyl acetatelayers were combined and evaporated to give the required product (6.404g).

¹H NMR 8 (d₆-DMSO): 4.74 (m, 4H), 5.08 (s, 2H), 6.67 (s, 1H), 6.67 (s,1H), 7.23 (s, 1H), 7.37 (m, 5H). m/z 231 (M−H)⁻

Methyl3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoate

DIAD (7.63 mL, 38.7 mmol) was added in a dropwise fashion to a solutionof methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (5.00 g, 19.4 mmol),1,3-difluoropropan-2-ol (3 mL, 38.7 mmol), and triphenylphosphine (10.16g, 38.7 mmol) in THF (100 mL) under an inert atmosphere at 0° C. Thesolution was allowed to reach RT and left to stir for 2 days. The THFwas removed in vacuo and the residual oil slurried with a mixture of 20%ethyl acetate in isohexane. After allowing to stir for 90 minutes themixture was filtered and the filtrate evaporated. The residual was oilchromatographed on silica, eluting with 30% ethyl acetate in isohexane,to give the desired compound (7.41 g).

¹H NMR 5 (d₆-DMSO): 3.85 (s, 3H), 4.71 (m, 4H), 5.03 (m, 1H), 5.17 (s,2H), 7.01 (t, 1H), 7.20 (m, 2H), 7.40 (m, 5H). m/z 335 (M−H)⁻

The preparation of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate isdescribed above.

EXAMPLE 103-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A solution of3-hydroxy-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(116 mg, 0.4 mmol) and the5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (111 mg, 0.48 mmol) inacetonitrile (2 mL) containing potassium carbonate (111 mg, 0.8 mmol)was heated with stirring in the microwave reactor for 6 hours at 160° C.The reaction mixture was filtered and the filtrate evaporated to drynessunder reduced pressure and purified by chromatography on silica, elutingwith 50-100% ethyl acetate in hexane, to give the required product (177mg).

¹H NMR δ (CDCl₃): 0.91 (t, 3H), 1.25 (d, 3H), 1.52-1.75 (m, 2H), 2.32(quin, 2H), 3.72 (s, 3H), 4.17 (t, 2H), 4.25-4.34 (m, 3H), 6.73 (d, 1H),6.81 (t, 1H), 7.12 (s, 1H), 7.21 (d, 1H), 7.24 (s, 1H), 8.09 (d, 1H),8.18 (d, 1H), 8.54 (s, 1H); m/z 484 (M+H)⁺

The preparation of 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine wasdescribed earlier. The preparation of3-hydroxy-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideis described below:

3-Hydroxy-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-ylbenzamide

A solution of3-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(900 mg) in THF (5 mL) and ethanol (5 mL) containing 10% palladium oncarbon was stirred under an atmosphere of hydrogen overnight. Thepalladium on carbon was removed by filtration and the filtrateevaporated under reduced pressure to give the required compound as awhite solid (683 mg). ¹H NMR δ (CDCl₃): 0.95 (t, 3H), 1.27 (d, 3H),1.54-1.80 (m, 2H), 3.79 (s, 3H), 4.31 (q, 1H), 6.57 (t, 1H), 6.81 (d,1H), 6.96 (s, 1H), 6.98 (s, 1H), 7.30 (s, 1H), 7.57 (s, 1H), 8.84 (s,1H); m/z 290 (M+H)⁺

3-{[(1S)-1-Methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide

HATU (1.19 g, 3.13 mmol) was added to3-{[(1S)-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (750 mg,2.5 mmol) and 3-amino-1 methylpyrazole (291 mg, 3 mmol) in DMF (5 mL)followed by addition of DIPEA (0.807 mL, 6.25 mmol) and the reaction wasstirred for 16 hours. The reaction mixture was added to ethyl acetate(30 mL), washed with water (10 mL), 2N citric acid (10 mL), saturatedaqueous sodium hydrogencarbonate (10 mL) and brine (10 mL), then dried(MgSO₄), filtered and evaporated to a gummy residue. The residue wastaken up in 50% ether in ethylacetate (50 mL), washed with 2Nhydrochloric acid (10 mL), water (10 mL), saturated aqueous sodiumhydrogencarbonate (10 mL) and brine (10 mL) then dried (MgSO₄), filteredand evaporated to a foam (900 mg) which was used without furtherpurification in the next step. ¹H NMR δ (CDCl₃): 0.96 (t, 3H), 1.28 (d,3H), 1.51-1.80 (m, 2H), 3.78 (s, 1H), 4.31 (q, 1H), 5.06 (s, 2H), 6.68(t, 1H), 6.82 (d, 1H), 7.00 (s, 1H), 7.06 (s, 1H), 7.29 (s, 3H),7.31-7.47 (m, 5H), 8.63 (s, 1H); m/z 380 (M+H)⁺

3-{[(1S)-1-Methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoic acid

Methyl 3-{[(1S)-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoate (14.87g, 47.36 mmol) was vigorously stirred in a mixture of aqueous 1M sodiumhydroxide (120 mL) and THF at approximately 45° C. for 4 hours. The bulkof the THF was removed under reduced pressure and the resultant solutionpartitioned between water and diethyl ether. The aqueous phase wasacidified with 2M hydrochloric acid and then extracted with ethylacetate. The organics were dried (MgSO₄) and concentrated in vacuo gavea white solid (11.5 g). ¹H NMR δ (CDCl₃): 0.90 (t, 3H), 1.20 (d, 3H),1.49-1.69 (m, 2H), 4.33-4.46 (m, 1H), 5.12 (s, 2H), 6.75-6.79 (m, 1H),6.99-7.03 (m, 1H), 7.06-7.11 (m, 1H), 7.26-7.47 (m, 5H)

Methyl 3-{[(1S)-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoate

A solution of DIAD (16.6 mL, 84.0 mmol) in dry THF (100 mL) was addeddropwise to a cooled (ice bath) stirred mixture of methyl3-hydroxy-5-{[phenylmethyl]oxy}benzoate (14.5 g, 56.2 mmol);R-(−)-sec-butanol (5 g, 67.0 mmol) and solid-supportedtriphenylphosphine (28 g, of 3 mmol per g loading, 84.0 mmol) in dry THF(400 mL) whilst maintaining the temperature below 10° C. The mixture wasallowed to stir for 3 hours, then diluted with diethyl ether (800 mL)and filtered. Removal of the solvent gave a pale coloured oil, which waspurified by column chromatography on silica, eluting with 25% ethylacetate in hexane; to give the desired product (14.87 g).

¹H NMR δ (CDCl₃): 0.99 (t, 3H), 1.28 (d, 3H), 1.53-1.80 (m, 2H), 3.89(s, 3H), 4.25-4.42 (m, 1H), 5.07 (s, 2H), 6.68-6.81 (m, 1H), 7.17-7.53(m, 7H); m/z 313 (M−H)⁻

The preparation of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate wasdescribed earlier.

EXAMPLE 113-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

HATU (34 mg, 0.89 mmol) was added to5-[(3-{[(1S)-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid (190 mg, 0.4 mmol) and azetidine hydrochloride (84 mg, 0.89 mmol)in DMF (5 mL). DIPEA (0.311 mL, 1.79 mmol) was added and the reactionwas stirred for 16 hours. The reaction mixture was added to ethylacetate (20 mL), washed with water (10 mL), 2N citric acid (10 mL),saturated aqueous sodium hydrogencarbonate (10 mL) and brine (10 mL),then dried (MgSO₄), filtered and evaporated under reduced pressure to agummy residue. The residue was purified by chromatography on silica,eluting with 50-100% ethyl acetate in hexane, to give a gum which wastaken up in 50% ethyl acetate in ether and washed twice with water,brine (10 mL) then dried (MgSO₄) to give the desired product as a foam(58 mg).

¹H NMR δ (CDCl₃): 0.91 (t, 3H), 1.25 (d, 3H), 1.51-1.75 (m, 2H), 2.31(quin, 2H), 3.72 (s, 3H), 4.19 (t, 2H), 4.29 (q, 1H), 4.62 (t, 2H), 6.73(d, 1H), 6.80 (t, 1H), 7.13 (t, 1H), 7.21 (d, 1H), 7.23 (t, 1H), 8.26(s, 1H), 8.52 (s, 1H), 8.79 (s, 1H); m/z 451 (M+H)⁺

The preparation of5-[(3-{[(18)-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid is described below:

5-[(3-{[(1S)-1-Methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid

A solution of3-hydroxy-5-{[(S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(116 mg, 0.4 mmol) and the methyl 5-chloropyrazine-2-carboxylate (83 mg,0.48 mmol) in acetonitrile (2 mL) containing potassium carbonate (111mg, 0.8 mmol) was heated with stirring in the microwave for 6 hours at160° C. Analytical LC-MS showed formation of the acid but no ester. Thereaction mixture was dissolved in water (10 mL), acidified with 2Ncitric acid and extracted with ethyl acetate (5×20 mL), washed withbrine, dried (MgSO₄) and evaporated to dryness under reduced pressure todeliver the desired product (190 mg) which was used without purificationin the next step.

m/z 412 (M+H)⁺

The preparation of3-hydroxy-5-{[(S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamidewas described earlier.

EXAMPLE 123-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A mixture of3-hydroxy-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(0.116 g, 0.4 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (116 mg,0.48 mmol), cesium carbonate (392 mg, 1.2 mmol) andbromotris(triphenylphosphine)copper(I) (38 mg, 0.04 mmol) in DMA (5 mL)was stirred in the microwave reactor at 160° C. for 4 hours. The productwas dissolved in ethyl acetate (20 mL) and water (15 mL) and the layersseparated. The organic layer was washed with brine (50 mL), dried(MgSO₄), filtered and the solvent removed in vacuo to give a brown oilwhich was chromatographed on silica, eluting with a gradient of 0-5%methanol in ethyl acetate, and then re-columned on silica, eluting witha gradient of 0-5% methanol in DCM, to give the desired compound as awhite foam which crystallised on standing. The material was trituratedwith 50% ethyl acetate in hexane to give the required product as a whitesolid (95 mg). ¹H NMR δ (CDCl₃): 0.90 (t, 3H), 1.23 (d, 3H), 1.51-1.72(m, 2H), 2.28 (quin, 2H), 3.73 (s, 3H), 4.18 (t, 2H), 4.28 (q, 1H), 4.64(t, 2H), 6.67 (t, 1H), 6.72 (d, 1H), 6.99 (s, 1H), 7.15 (s, 1H), 7.22(d, 1H), 7.31 (d, 1H), 8.04 (d, 1H), 8.26 (s, 1H), 8.41 (s, 1H); m/z 450(M+H)⁺

The preparation of3-hydroxy-5-{[(is)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideand 2-(azetidin-1-ylcarbonyl)-5-bromopyridine were described earlier.

EXAMPLE 133-{[2-(Azetidin-1-ylcarbonyl)pyrimidin-5-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A mixture of3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide(250 mg, 0.91 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyrimidine (242mg, 1.0 mmol), cesium carbonate (886 mg, 2.72 mmol) andbromotris(triphenylphosphine)copper(I) (423 mg, 0.45 mmol) in DMA (5 mL)was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 4 hours.The mixture was added to ethyl acetate (50 mL) and water (50 mL), theorganic layer washed with brine (50 mL), dried (MgSO₄), filtered and thesolvent removed in vacuo to give a brown oil. The residue waschromatographed on silica, eluting with a gradient of 0-10% methanol inethyl acetate, to give the desired compound (199 mg).

¹H NMR δ (CDCl₃): 1.39 (d, 6H), 2.40 (quin, 2H), 3.82 (s, 3H), 4.35 (t,2H), 4.62 (mult, 1H), 4.68 (t, 2H), 6.79 (s, 1H), 6.84 (s, 1H), 7.20 (s,1H), 7.33 (mult, 2H), 8.60 (s, 2H), 8.97 (s, 1H); m/z 437 (M+H)⁺

The following compound was synthesised in an analogous fashion from3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide.

Example Structure m/z NMR 13a

467(M + H)⁺ ¹H NMR δ (CDCl₃): 1.33 (d, 3 H), 2.37(quin, 2 H), 3.41 (s, 3H), 3.48-3.60 (m,2 H), 3.78 (s, 3 H), 4.30 (t, 2 H), 4.58(mult, 1 H),4.64 (t, 2 H), 6.80 (d, 1 H),6.83 (t, 1 H), 7.19 (s, 1 H), 7.30 (d, 1H),7.33 (s, 1 H), 8.55 (s, 2 H), 8.93 (s, 1 H)

The preparation of3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamidewere described earlier.

The preparation of 2-(azetidin-1-ylcarbonyl)-5-bromopyridine isdescribed below:

2-(Azetidin-1-ylcarbonyl)-5-bromopyrimidine

Oxalyl chloride (1.50 mL, 16.8 mmol) then DMF (2 drops) were added to amixture of 5-bromopyrimidine-2-carboxylic acid (prepared according toliterature procedure described in WO 2005/028452) (2.86 g, 14.0 mmol) inDCM (40 mL). The reaction mixture was stirred at RT for 2 hours, thevolatiles removed in vacuo and the residue dissolved in DCM (40 mL).Azetidine hydrochloride (1.44 g, 15.4 mmol) followed by triethylamine(4.29 mL, 30.8 mmol) were added and the mixture stirred at RT for 72hours. The mixture was concentrated in vacuo and ethyl acetate (100 mL)added to the residue. The organics were washed with water (100 mL),citric acid solution (50 mL), saturated sodium bicarbonate solution (50mL), brine (50 mL), dried (MgSO₄), filtered and the solvent removed invacuo to give a yellow solid which was chromatographed on silica,eluting with a gradient of 50-100% ethyl acetate in isohexane, to givethe desired compound (0.86 g). ¹H NMR δ (CDCl₃): 2.39 (quin, 2H), 4.32(t, 2H), 4.63 (t, 2H), 8.92 (s, 2H); m/z 242, 244 (M+H)⁺

EXAMPLE 143-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A mixture3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide(100 mg, 0.32 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (86 mg,0.35 mmol), cesium carbonate (209 mg, 0.64 mmol) andbromotris(triphenylphosphine)copper(I) (150 mg, 0.16 mmol) in DMA (5 mL)was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 3 hours.The reaction mixture was added to ethyl acetate (50 mL) and water (50mL), the organic layer washed with brine (50 mL), dried (MgSO₄),filtered and the solvent removed in vacuo to give a brown oil. Theresidue was chromatographed on silica, eluting with 0-100% ethyl acetatein isohexane, to give a colorless oil which appeared to be a mixture ofproduct and eliminated product(3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[1-(fluoromethyl)ethenyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide).This mixture was dissolved in chloroform (5 mL), TFA (0.5 mL) added andthe mixture stirred for 2 hours. Complete degradation of eliminatedproduct was observed by LCMS and the mixture concentrated in vacuo thenwater added. The mixture was neutralised and extracted into ethylacetate (2×30 mL), washed with brine (30 mL), dried (MgSO₄), filteredand reduced to give a yellow oil which was chromatographed on silica,eluting with 0-100% ethyl acetate in isohexane, to give the desiredcompound (13 mg).

¹H NMR δ (CDCl₃): 2.29 (quin, 2H), 3.76 (s, 3H), 4.19 (t, 2H), 4.55(mult, 2H), 4.67 (mult, 5H), 6.72 (s, 1H), 6.80 (mult, 1H), 7.09 (s,1H), 7.25 (mult, 2H), 7.32 (mult, 1H), 8.06 (d, 1H), 8.26 (d, 1H), 8.43(s, 1H); m/z 472 (M+H)⁺

The preparation of3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamideand 2-(azetidin-1-ylcarbonyl)-5-bromopyridine were described earlier.

EXAMPLE 153-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

DIPEA (0.45 mL, 2.58 mmol) was added to a mixture of5-[(3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid (0.28 g, 0.65 mmol), azetidine hydrochloride (121 mg, 1.29 mmol)and HATU (516 mg, 1.36 mmol) in DMF (5 mL) and stirred at RT for 72hours. Ethyl acetate (40 mL) was added and the organics washed withwater (2×30 mL), brine (30 mL), dried (MgSO₄), filtered and reduced invacuo to give a yellow oil which was chromatographed on silica, elutingwith 0-100% ethyl acetate in isohexane, to give the desired compound(109 mg). ¹H NMR δ (CDCl₃): 2.32 (quin, 2H), 3.70 (s, 3H), 4.19 (t, 2H),4.54-4.72 (m, 7H), 6.73 (s, 1H), 6.93 (t, 1H), 7.22 (d, 1H), 7.25 (s,1H), 7.34 (s, 1H), 8.28 (d, 1H), 8.78 (d, 1H), 8.80 (s, 1H); m/z 473(M+H)⁺

The following compound was synthesised in an analogous fashion from5-[(3-[(1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid.

Example Structure m/z NMR 15a

437(M + H)⁺ ¹H NMR δ (CDCl₃): 1.38 (d, 6 H), 2.40(quin, 2 H), 3.83 (s, 3H), 4.28 (t, 2 H),4.62 (sept, 1 H), 4.71 (t, 2 H), 6.82 (s, 1 H),6.89(t, 1 H), 7.23 (s, 1 H), 7.31 (m, 2 H),8.35 (s, 1 H), 8.55 (s, 1 H),8.88 (s, 1 H)

The preparation of5-[(3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid is described below:

5-[(3-{[2-Fluoro-1-(fluoromethyl)ethyl]oxy}-5-1{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid

Lithium hydroxide monohydrate (77 mg, 1.82 mmol) in water (2 mL) wasadded to methyl5-[(3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate(325 mg, 0.73 mmol) in THF (4 mL) and the mixture stirred at RT for 20hours. The THP was removed in vacuo and the aqueous residue washed withethyl acetate to remove impurities then acidified with 1M citric acid.Ethyl acetate was added and a white solid removed by filtration anddried in vacuo to give the desired compound as a white solid (0.28 g).¹H NMR δ (d₆-DMSO): 3.79 (s, 3H), 4.77 (m, 4H), 5.12 (t, 1H), 6.59 (s,1H), 7.22 (s, 1H), 7.50 (s, 1H), 7.62 (s, 2H), 8.69 (s, 1H), 8.80 (s,1H), 10.90 (s, 1H), 13.50 (s, 1H), m/z 434 (M+H)⁺

5-[(3-[(1-Methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid, used in the preparation of Example 15a, was prepared in ananalogous fashion from methyl5-[(3-[(1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate.

Structure m/z NMR

398(M +H)⁺

The preparation of methyl5-[(3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylateis described below:

Methyl5-[(3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate

A mixture of3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide(250 mg, 0.8 mmol), methyl 5-chloropyrazine-2-carboxylate (208 mg, 1.20mmol) and potassium carbonate (222 mg, 1.61 mmol) in acetonitrile (5 mL)was stirred in a ‘Biotage initiator Microwave’ at 120° C. for 3 hours.The solvent was removed in vacuo and the residue dissolved in ethylacetate (50 mL) and water (50 mL), the organic layer washed with brine(50 mL), dried (MgSO₄), filtered and the solvent removed in vacuo togive a yellow oil which was chromatographed on silica, eluting with0-100% ethyl acetate in isohexane, to give the desired compound (0.325g). ¹H NMR δ (CDCl₃): 3.71 (s, 3H), 3.96 (s, 3H), 4.56 (m, 2H), 4.68 (m,3H), 6.73 (s, 1H), 6.95 (s, 1H), 7.22 (s, 1H), 7.27 (s, 1H), 7.36 (s,1H), 8.46 (s, 1H), 8.67 (s, 1H), 8.67 (s, 1H); m/z 448 (M+H)⁺

Methyl5-[(3-[(1-methylethyl)oxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate,used in Example 15a, was prepared in an analogous fashion from3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide.

Structure m/z NMR

412(M + H)⁺

The preparation of3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamidewere described previously.

EXAMPLE 163-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A mixture of3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide(110 mg, 0.32 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (75mg, 0.32 mmol) and potassium carbonate (89 mg, 0.64 mmol) inacetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate(50 mL) added to the residue which was washed with water (20 mL), brine(50 mL), dried (MgSO₄), filtered and the solvent removed in vacuo togive a yellow oil. The residue was chromatographed on silica, elutingwith a gradient of 50-100% ethyl acetate in isohexane, to give thedesired compound (92 mg). ¹H NMR δ (CDCl₃): 1.40 (d, 3H), 2.41 (quin,2H), 3.81 (s, 3H), 4.01 (mult, 2H), 4.26 (t, 2H), 4.38 (t, 2H), 4.67(sextet, 1H), 6.29 (t, 1H), 6.82 (d, 1H), 6.96 (t, 1H), 7.27 (t, 1H),7.31 (d, 1H), 7.38 (t, 1H), 8.18 (d, 1H), 8.26 (d, 1H), 8.77 (s, 1H),m/z 536 (M+H)⁺

The following compound was made in an analogous fashion from3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamideand 5-(azetidin-1-ylcarbonyl)-2-chloropyridine.

Example Structure m/z NMR 16a

502(M + H)⁺ ¹H NMR δ (CDCl₃): 1.37 (d, 3 H), 2.38(quin, 2 H), 3.73 (s, 3H), 3.98 (m, 2 H), 4.25(t, 2 H), 4.36 (t, 2 H), 4.62 (sextet, 1 H),6.27(t, 1 H), 6.81 (d, 1 H), 6.90 (t, 1 H), 7.00 (d,1 H), 7.24 (t, 1 H),7.27 (m, 1 H), 7.33 (m,1 H), 8.08 (m, 1 H), 8.42 (d, 1 H), 9.12 (s, 1 H)

The preparation of 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine and5-(azetidin-1-ylcarbonyl)-2-chloropyridine were described earlier.

The preparation of3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamideis described below:

3-({(1S)-2-[(Difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide

3-({(1S)-2-[(Difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(0.1 g, 0.23 mmol) was dissolved in ethanol (3 mL) and THF (3 mL) andthe flask evacuated and purged with argon (3 times). 10% Palladium oncarbon (0.01 g) was added and the flask further evacuated and finallypurged with hydrogen gas. The reaction mixture was stirred at RT for 20hours until completion. The reaction mixture was evacuated and purgedwith nitrogen (3 times). The catalyst was filtered off through celiteand the filtrate concentrated in vacuo to give the desired compound (70mg). ¹H NMR δ (CDCl₃): 1.28 (d, 3H), 3.71 (s, 3H), 3.80-3.95 (m, 2H),4.51 (sextet, 1H), 5.96-6.36 (t, 1H), 6.53 (s, 1H), 6.73 (s, 1H), 6.91(s, 1H), 6.96 (s, 1H), 7.22 (s, 1H), 8.83 (s, 1H). m/z 342 (M+H)⁺.

3-({(1S)-2-[(Difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide

DIPEA (0.198 mL, 1.14 mmol) was added to a mixture of3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-[(phenylmethyl)oxy]benzoicacid (0.1 g, 0.28 mmol), 3-amino-1-methylpyrazole (39 mg, 0.4 mmol) andHATU (0.227 g, 0.6 mmol) in DMF (3 mL) and stirred at RT for 20 hours.Ethyl acetate (30 mL) was added and the mixture washed with water (30mL), brine (30 mL), dried (MgSO₄), filtered and reduced in vacuo to givea yellow oil which was chromatographed on silica, eluting with agradient of 0-100% ethyl acetate in isohexane, to give the desiredcompound (0.1 g).

¹H NMR δ (CDCl₃): 1.36 (d, 3H), 3.68 (s, 3H), 3.82-3.95 (m, 2H), 4.48(sex, 1H), 5.00 (s, 2H), 6.19 (t, 1H), 6.63 (s, 1H), 6.73 (s, 1H), 6.93(s, 1H), 7.03 (s, 1H), 7.28 (m, 1H), 7.35 (m, 5H), 8.59 (s, 1H). m/z 432(M+H)⁺.

3-({(1S)-2-[(Difluoromethyl)oxy]-1-methylethyl}oxy)-5-[(phenylmethyl)oxy]benzoicacid

Lithium hydroxide monohydrate (19 mg, 0.45 mmol) in water (2 mL) wasadded to methyl3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-[(phenylmethyl)oxy]benzoate(0.11 g, 0.3 mmol) in THF (4 mL) and the mixture stirred at RT for 20hours. The THF was removed in vacuo and the aqueous layer adjusted topH3 with citric acid then extracted into ethyl acetate (2×30 mL). Theorganics were washed with water (30 mL), brine (30 mL), dried (MgSO₄),filtered and the solvent removed in vacuo to give the desired compound(0.1 g).

¹H NMR δ (d₆-DMSO): 1.27 (d, 3H), 4.00 (m, 2H), 4.75 (sextet, 1H), 5.15(s, 2H), 6.72 (t, 1H), 7.08 (t, 1H), 7.16 (t, 1H), 7.41 (m, 5H), 12.95(s, 1H). m/z 351 (M+H)⁺.

Methyl3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-[(phenylmethyl)oxy]benzoate

2-(Fluorosulphonyl)difluoroacetic acid (0.239 mL, 2.31 mmol) was addeddropwise, with stirring, to a degassed mixture of methyl3-{[(1S)-2-hydroxy-1-methylethyl]oxy}-5-[(phenylmethyl)oxy]benzoate(0.73 g, 2.31 mmol) and copper (I) iodide (88 mg, 0.46 mmol) inacetonitrile (10 mL) at 45° C. The reaction was stirred at 45° C. for 24hours. The solvent was removed in vacuo and ethyl acetate (30 mL) added.The organics were washed with water (30 mL), brine (30 mL), dried(MgSO₄), filtered and the solvent removed in vacuo to give a yellow oilwhich was chromatographed on silica, eluting with a gradient of 0-30%ethyl acetate in isohexane, to give the desired compound (0.11 g).

¹H NMR δ (CDCl₃): 1.37 (d, 3H), 3.93 (s, 3H), 4.00 (m, 2H), 4.63(sextet, 1H), 5.10 (s, 2H), 6.28 (t, 1H), 6.77 (t, 1H), 7.28 (t, 1H),7.41 (m, 6H). In/z 367 (M+H)⁺.

Methyl3-{[(1S)-2-hydroxy-1-methylethyl]oxy}-5-[(phenylmethyl)oxy]benzoate

Benzyl bromide (1.89 g, 7.20 mmol) was added to a mixture of methyl3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate (1.55 g, 6.86 mmol)and potassium carbonate (1.89 g, 0.014 mol) in DMF (16 mL) and thereaction stirred at RT for 20 hours. Ethyl acetate (40 mL) was added andthe mixture washed with water (40 mL), saturated sodiumbicarbonatesolution (40 mL), brine (40 mL), dried (MgSO₄), filtered and the solventremoved in vacuo to give a red oil which was chromatographed on silica,eluting with a gradient of 0-100% ethyl acetate in isohexane, to givethe desired compound (1.7 g).

¹H NMR δ (CDCl₃): 1.30 (d, 3H), 1.95 (m, 1H), 3.76 (m, 2H), 3.92 (s,3H), 4.53 (m, 1H), 5.11 (s, 2H), 6.78 (t, 1H), 7.25 (m, 1H), 7.32 (m,1H), 7.45 (m, 5H). m/z 317 (M+H)⁺.

Methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate

Trimethylsilyl iodide (115 mL, 0.79 mol) was added to a solution ofmethyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (38.01 g,0.158 mol) in acetonitrile (500 mL) and stirred for 24 hours. Methanol(300 mL) was added and the reaction stirred for 10 mins. 10% w/v Aqueoussodium thiosulfate pentahydrate (100 mL) was added to the mixture andstirred for 20 mins. The reaction mixture was neutralised with saturatedaqueous sodium bicarbonate solution, the organic solvents removed invacuo, and the product extracted into ethyl acetate (4×100 mL). Thecombined organic layers were dried (MgSO₄), filtered and the solventsremoved in vacuo. The crude material was crystallised from ethyl acetateto give the title compound (16.80 g).

¹H NMR δ (d₆-DMSO): 1.18 (d, 3H), 3.40-3.55 (m, 2H), 3.80 (s, 3H), 4.35(sex, 1H), 4.80 (t, 1H), 6.57 (m, 1H), 6.90 (m, 2H), 9.75 (s, 1H). m/z304 (M+H)⁺

Methyl 3-Hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate

Methyl3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoate(50.0 g, 0.152 mmol) was dissolved in a mixture of THF:ethanol (600 mL)and the flask evacuated and purged with nitrogen (3 times). 10%Palladium on carbon (5.0 g) was added and the flask further evacuatedand finally purged with hydrogen gas. The reaction mixture was stirredat ambient temperature for 20 hours until completion. The reactionmixture was evacuated and purged with nitrogen (3 times). The catalystwas filtered off, and the filtrate concentrated in vacuo to give thedesired compound (36.7 g).

¹H NMR δ (d₆-DMSO): 1.2 (d, 3H), 3.25 (s, 3H), 3.44 (m, 2H), 3.82 (s,3H), 4.55 (m, 1H), 6.6 (s, 1H), 6.9 (s, 1H), 6.95 (s, 1H), 9.8 (s, 1H).The preparation of methyl3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoate wasdescribed previously.

EXAMPLE 173-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A mixture of3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide(220 mg, 0.64 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (171 mg,0.71 mmol), cesium carbonate (419 mg, 1.29 mmol) andbromotris(triphenylphosphine)copper(I) (300 mg, 0.32 mmol) in DMA (5 mL)was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 4 hours.The reaction mixture was added to ethyl acetate (50 mL) and water (50mL), the organic layer washed with brine (50 mL), dried (MgSO₄),filtered and the solvent removed in vacuo to give a brown oil. Theresidue was chromatographed on silica, eluting with 0-100% ethyl acetatein isohexane, to give the desired compound (102 mg).

¹H NMR δ (CDCl₃): 1.28 (d, 3H), 2.28 (quin, 2H), 3.68 (s, 3H), 3.90(mult, 2H), 4.17 (t, 2H), 4.54 (sextet, 1H), 4.63 (t, 2H), 6.19 (t, 1H),6.71 (t, 1H), 6.73 (s, 1H), 7.06 (s, 1H), 7.22 (mult, 2H), 7.30 (mult,1H), 8.04 (d, 1H), 8.24 (d, 1H), 8.84 (s, 1H); m/z 502 (M+H)⁺

The preparation of3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamideand 2-(azetidin-1-ylcarbonyl)-5-bromopyridine were described earlier.

EXAMPLE 183-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

DIPEA (0.41 mL, 2.33 mmol) was added to a mixture of5-[(3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid (0.27 g, 0.58 mmol), azetidine hydrochloride (109 mg, 1.17 mmol)and HATU (466 mg, 1.22 mmol) in DMF (5 mL) and stirred at RT for 24hours. Ethyl acetate (40 mL) was added and the organics washed withwater (2×30 mL), brine (30 mL), dried (MgSO₄), filtered and concentratedin vacuo to give a yellow oil. The residue was chromatographed onsilica, eluting with 0-5% methanol in ethyl acetate, to give the desiredcompound (124 mg).

¹H NMR δ (CDCl₃): 1.28 (d, 3H), 2.30 (quin, 2H), 3.65 (s, 3H), 3.90 (m,2H), 4.18 (t, 2H), 4.53 (sextet, 1H), 4.61 (t, 2H), 6.19 (t, 1H), 6.73(d, 1H), 6.84 (t, 1H), 7.18 (m, 2H), 7.28 (s, 1H), 8.25 (s, 1H), 8.76(s, 1H), 9.14 (s, 1H); m/z 503 (M+H)⁺.

The preparation of5-[(3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid is described below:

5-[(3-({(1S)-2-[(Difluoromethyl)oxy]-1-methylethyl}oxy)-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid

A mixture of3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide(220 mg, 0.64 mmol), methyl 5-chloropyrazine-2-carboxylate (112 mg, 0.64mmol) and potassium carbonate (178 mg, 1.29 mmol) in acetonitrile (5 mL)was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 4 hours.The solvent was removed in vacuo and water (20 mL) added. The mixturewas adjusted to pH3 with 1M citric acid and extracted into ethyl acetate(2×50 mL). The combined organics were washed with water (20 mL), brine(50 mL), dried (MgSO₄), filtered and the solvent removed in vacuo togive a yellow oil (0.19 g) which appeared to be a mixture of the acidand methyl ester. Lithium hydroxide monohydrate (26 mg, 0.60 mmol) inwater (3 mL) was added to the mixture of acid and ester (0.19 g, 0.4mmol) in THF (6 mL) and the mixture stirred at RT for 72 hours. Theorganics were removed in vacuo and the residue adjusted to pH3 with 1Mcitric acid, twice extracted into ethyl acetate and the combinedorganics, washed with water (30 mL), brine (30 mL), dried (MgSO₄),filtered and the solvent removed in vacuo to give the desired compoundas a yellow solid (0.17 g).

m/z 464 (M+H)⁺

The preparation of3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamidewas described earlier.

EXAMPLE 193-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(1:1)

A solution of 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (95 mg,0.44 mmol), a mixture of3-hydroxy-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-hydroxy-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(1:1) (129 mg, 0.42 mmol) and potassium carbonate (146 mg, 1.05 mmol) inacetonitrile (3 mL) was heated in a microwave reactor at 160° C. for 5hours. The acetonitrile was removed in vacuo and the residue dissolvedin ethyl acetate (25 mL). The organic solution was washed with water (25mL), brine (25 mL), dried (MgSO₄) and evaporated to a residue which waschromatographed on alumina, eluting with a gradient of 0-5% methanol inethyl acetate, to give the required product (56 mg).

¹H NMR δ (CDCl₃): 1.18 (m, 6H), 2.32 (m, 3H), 3.66 (s, 3H), 3.79 (quin,1H), 4.15 (m, 3H), 4.28 (t, 2H), 6.72 (d, 1H), 6.85 (t, 1H), 7.17 (s,1H), 7.19 (s, 1H), 7.29 (s, 1H), 8.08 (m, 1H), 8.15 (m, 1H), 9.10 (s,1H); m/z 501 (M+H)⁺

This mixture of diasteromers were separated by chiral preparatory HPLCon a Chiralpak IA (250 mm×20 mm) No. EG014 column, eluting with amixture of isohexane/ethyl acetate/acetic acid/triethylamine(40/60/0.2/0.1) to give the first eluted isomer (43 mg), Example 19a,and the second eluted isomer (40 mg), Example 19b.

The preparation of 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine wasdescribed earlier.

The preparation of3-hydroxy-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-hydroxy-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(1:1) is described below:

3-Hydroxy-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-hydroxy-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(1:1)

A solution of a mixture of3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamideand3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(1:1) (1.26 g, 3.19 mmol) and 10% by weight palladium on carbon (0.13 g)in ethanol (50 mL) was allowed to stir at RT under a hydrogen atmospherefor 16 hours. The solution was filtered through Celite® and washedthrough with methanol (100 mL). The solution was concentrated in vacuoto give the desired compound (1.03 g). ¹H NMR 5 (d₆-DMSO): 1.09 (d, 3H),1.17 (d, 3H), 3.76 (m, 1H), 3.78 (s, 3H), 4.34 (quin, 1H), 6.48 (t, 1H),6.56 (d, 1H), 6.93 (t, 1H), 7.05 (t, 1H), 7.60 (d, 1H), 9.66 (s, 1H),10.67 (s, 1H); m/z 306 (M+H)⁺

3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamideand3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(1:1)

A solution of a mixture of3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoicacid and3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoicacid (1:1) (2.50 g, 7.92 mmol), 1-methyl-1H-pyrazol-3-amine (1.54 g,15.8 mmol), HATU (3.92 g, 10.3 mmol) and DIPEA (2.76 mL, 15.8 mmol) inDMF (15 mL) was stirred at RT and under ambient atmosphere for 16 hours.Water (150 mL) was added and the solution extracted with ethyl acetate(250 mL). The ethyl acetate layer was washed with brine and dried(MgSO₄), and evaporated to a residue which was chromatographed onsilica, eluting with 50% ethyl acetate in hexane, to give the desiredproduct (1.26 g). ¹H NMR δ (CDCl₃): 1.17 (s, 3H), 1.18 (s, 3H), 2.44 (d,1H), 3.70 (s, 3H), 3.77 (m, 1H), 4.10 (quin, 1H), 4.99 (s, 2H), 6.64 (t,1H), 6.75 (d, 1H), 6.96 (t, 1H), 7.03 (t, 1H), 7.22 (d, 1H), 7.31 (m,5H), 8.68 (s, 1H); m/z 396 (M+H)⁺

3-{[(1R,2R)-2-Hydroxy-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoicacid and3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoicacid (1:1)

To a solution of a mixture of methyl3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoateand methyl3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoate(1:1) (2.52 g, 7.63 mmol) in THF (40 mL) was added a solution of lithiumhydroxide monohydrate (0.80 g, 19.07 mmol) in water (10 mL). The mixturewas allowed to stir at RT for 16 hours. The THF was removed in vacuo andthe resulting solution was partitioned between water (100 mL) and ethylacetate (250 mL). The ethyl acetate layer was washed with brine (50 mL)and dried (MgSO₄). The aqueous layer was then adjusted to pH 7 byaddition of 1M hydrochloric acid and extracted with ethyl acetate (75mL). The ethyl acetate layer was washed with brine and dried (MgSO₄).The ethyl acetate layers were combined and evaporated to give therequired product (2.50 g).

¹H NMR δ (CDCl₃): 1.18 (s, 3H), 1.20 (s, 3H), 3.80 (quin, 1H), 4.14(quin, 1H), 5.01 (s, 2H), 6.72 (t, 1H), 7.21 (m, 1H), 7.32 (m, 6H).

Methyl3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoateand methyl3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-5-[(phenylmethyl)oxy]benzoate(1:1)

A solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (3.00 g,11.61 mmol), (2R,3S)-2,3-dimethyloxirane (3.04 mL, 34.8 mmol), andpotassium carbonate (4.02 g, 29.0 mmol) in acetonitrile (60 mL) washeated in a microwave reactor at 150° C. for 3 hours. The acetonitrilewas removed in vacuo and the residual oil dissolved in ethyl acetate (50mL), washed with water (50 mL), brine (50 mL), dried (MgSO₄) andevaporated to a residual oil. The residue was chromatographed on silica,eluting with ethyl acetate, to give the desired compound (2.52 g). ¹HNMR δ (CDCl₃): 1.17 (d, 6H), 3.82 (s, 3H), 4.04 (q, 2H), 4.99 (s, 2H),6.67 (t, 1H), 7.14 (s, 1H), 7.30 (m, 6H); m/z 330 (M−H)⁻

The preparation of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate wasdescribed earlier.

EXAMPLE 203-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide

A solution ofN-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide(128 mg, 0.4 mmol) and the5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (111 mg, 0.48 mmol) inacetonitrile (2 mL) containing potassium carbonate (111 mg, 0.8 mmol)was heated in a microwave reactor at 160° C. for 6 hours. The reactionmixture was filtered and the filtrate evaporated to dryness underreduced pressure and purified by chromatography on silica, eluting with50-100% ethyl acetate in hexane to give the required product as a whitefoam (176 mg).

¹H NMR δ (CDCl₃): 1.28 (d, 3H), 1.41 (t, 3H), 2.32 (quin, 2H), 3.35 (s,3H), 3.49 (m, 2H), 4.02 (q, 2H), 4.17 (t, 2H), 4.30 (t, 2H), 4.56 (q,1H), 6.76 (d, 1H), 6.88 (t, 1H), 7.18 (s, 1H), 7.28 (d, 1H), 7.32 (t,1H), 8.09 (d, 1H), 8.18 (d, 1H), 8.65 (s, 1H); m/z 514 (M+H)⁺

The preparation ofN-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamideis described below:

N-(1-Ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide

10% Palladium on carbon (1.9 g, 50% wet) was added under argon toN-(1-ethyl-1H-pyrazol-3-yl)-3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide(19.1 g, 46.7 mmol) in dry THF (100 mL) and ethanol (100 mL). Thereaction mixture was degassed, placed under a hydrogen balloon andstirred for 16 hours. The mixture was filtered through diatomaceousearth and the filtrate was evaporated to give a brown oil. The residuewas purified by column chromatography on silica, eluting with 40-65%ethyl acetate in hexanes, to give the desired product as a clear oilwhich crystallised on standing (11.35 g).

¹H NMR δ (CDCl₃): 1.21 (d, 6H), 1.38 (t, 3H), 3.32 (s, 3H), 3.39-3.51(m, 3H), 3.98 (q, 2H), 4.44-4.51 (m, 1H), 6.54 (s, 1H), 6.72 (d, 1H),6.92 (s, 2H), 7.26 (d, 1H), 8.18 (s, 1H), 8.85 (s, 1H); m/z 320 (M+H)⁺318 (M−H)⁻

N-(1-Ethyl-1H-pyrazol-3-yl)-3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide

HATU (23.5 g, 61.83 mmol) was added to3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid(16.28 g, 51.53 mmol) followed by addition of DMF (140 mL) and cooled to0° C. 1-Ethyl-1H-pyrazol-3-amine (6.86 g, 61.8 mmol) was added followedby DIPEA (21.3 mL) and the reaction stirred under argon, at 0° C., for 3hours. The solvent volume was reduced and the residue was dissolved inethyl acetate (500 mL), washed with citric acid (200 mL), sodiumhydrogen carbonate solution (150 mL) and saturated brine solution (2×150mL). The organic layer was separated and dried (MgSO₄), filtered andevaporated. Purification by column chromatography on silica, elutingwith 10-50% ethyl acetate in hexanes, afforded the title compound as apale yellow oil (19.1 g).

¹H NMR δ (CDCl₃): 1.23 (d, 3H), 1.38 (t, 3H), 3.33 (s, 3H), 3.42 (dd,1H), 3.50 (dd, 1H), 3.97 (q, 2H), 4.49 (sextet, 1H), 4.99 (s, 2H), 6.66(t, 1H), 6.75 (d, 1H), 6.98 (s, 1H), 7.02 (s, 1H), 7.26 (d, 1H),7.28-7.37 (m, 5H), 8.58 (s, 1H); m/z 410 (M+H)⁺

The preparation of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acidwas described earlier.

The preparation of 1-ethyl-1H-pyrazol-3-amine is described in theliterature [Chem. Heterocycl. Compd. (Engl. Transl.), 11, 1975, 212].

EXAMPLE 213-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide

A mixture ofN-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide(0.128 g, 0.4 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (116 mg,0.48 mmol), cesium carbonate (392 mg, 1.2 mmol) andbromotris(triphenylphosphine)copper(I) (38 mg, 0.04 mmol) in DMA (5 mL)was stirred in a microwave reactor at 160° C. for 4 hours. The productwas dissolved in ethyl acetate (20 mL) and water (15 mL) and the layersseparated. The organic layer washed with brine (50 mL), dried (MgSO₄),filtered and the solvent removed in vacuo to give a brown oil which waschromatographed on silica, eluting with a gradient of 70-100% ethylacetate in hexane to give the desired material as a clear foam (76 mg).¹H NMR δ (CDCl₃): 1.26 (d, 3H), 1.40 (t, 3H), 2.29 (quin, 2H), 3.34 (s,3H), 3.42-3.53 (m, 2H), 4.01 (q, 2H), 4.18 (t, 2H), 4.54 (q, 1H), 4.64(t, 2H), 6.74 (t, 2H), 7.04 (s, 1H), 7.22 (s, 1H), 7.27 (d, 1H), 7.30(d, 1H), 8.04 (d, 1H), 8.25 (d, 1H), 8.47 (s, 1H); m/z 480 (M+H)⁺

The preparation ofN-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamideand 2-(azetidin-1-ylcarbonyl)-5-bromopyridine was described earlier.

EXAMPLE 223-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide

HATU (304 mg, 0.80 mmol) was added to5-[(3-{[(1-ethyl-1H-pyrazol-3-yl)amino]carbonyl}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)oxy]pyrazine-2-carboxylicacid (0.4 mmol) and azetidine hydrochloride (75 mg, 0.89 mmol) in DMF (5mL) followed by addition of DIPEA (0.278 mL, 1.6 mmol) and the reactionwas stirred for 16 hours. The reaction mixture was added to ethylacetate (20 mL), the organic solution washed with water (10 mL), 2Ncitric acid (10 mL), saturated aqueous sodium hydrogencarbonate (10 mL)and brine (10 mL), then dried (MgSO₄), filtered and evaporated underreduced pressure to a gum. The residue was purified by chromatography onsilica, eluting with 70-100% ethyl acetate in hexane, to give thedesired compound as a white foam (98 mg). ¹H NMR δ (CDCl₃): 1.27 (d,3H), 1.40 (t, 3H), 2.31 (quin, 2H), 3.34 (s, 3H), 3.43-3.54 (m, 2H),4.01 (q, 2H), 4.19 (t, 2H), 4.54 (q, 1H), 4.62 (t, 2H), 6.73 (d, 1H),6.87 (t, 1H), 7.18 (t, 1H), 7.27 (d, 1H), 7.30 (t, 1H), 8.26 (d, 1H),8.49 (s, 1H), 8.78 (d, 1H); m/z 481 (M+H)⁺

The preparation of5-[(3-{[(1-ethyl-1H-pyrazol-3-yl)amino]carbonyl}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)oxy]pyrazine-2-carboxylicacid is described below:

5-[(3-{[(1-Ethel-1H-pyrazol-3-ylamino]carbonyl}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)oxy]pyrazine-2-carboxylicacid

A solution ofN-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide(128 mg, 0.4 mmol) and the methyl-5-chloropyrazine-2-carboxylate (83 mg,0.48 mmol) in acetonitrile (2 mL), containing potassium carbonate (111mg, 0.8 mmol), was heated in a microwave reactor at 160° C. for 6 hours.The reaction mixture was dissolved in water (10 mL), acidified with 2Ncitric acid and extracted with ethyl acetate (5×20 mL). The organicphase was washed with brine, dried (MgSO₄) and evaporated to drynessunder reduced pressure to give the desired material a yellow solid (164mg), which was used without purification in the next step. m/z 442(M+H)⁺

The preparation ofN-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamidewas described earlier.

EXAMPLE 233-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide

3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide(142 mg, 0.23 mmol) in methanol (2 mL) was stirred with 3.5Mhydrochloric acid (0.2 mL, 0.68 mmol) for 1 hour. The solution wasneutralised with saturated sodium bicarbonate solution and the organicsolvent was removed under reduced pressure. The residue was extractedwith ethyl acetate (3×10 mL), dried (MgSO₄), filtered and the solventremoved under reduced pressure. The residue was purified bychromatography on silica, eluting with 75-100% ethyl acetate in hexane,to give the required product as a white foam (99 mg).

¹H NMR δ (CDCl₃): 1.25 (d, 3H), 1.41 (d, 6H), 2.32 (quin, 2H), 3.67-3.71(m, 2H), 4.17 (t, 2H), 4.26-4.35 (m, 3H), 4.52 (q, 1H), 6.73 (s, 1H),6.87 (s, 1H), 7.19 (s, 1H), 7.30 (s, 1H), 7.32 (s, 1H), 8.10 (s, 1H),8.18 (s, 1H), 8.56 (s, 1H); m/z 514 (M+H)⁺

The preparation of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamideis described below:

3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((15)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide

A solution of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide(103 mg, 0.24 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine(66 mg, 0.29 mmol) in acetonitrile (2 mL), containing potassiumcarbonate (66 mg, 0.48 mmol), was heated in a microwave reactor at 160°C. for 6 hours. The reaction mixture was filtered and the filtrateevaporated to dryness under reduced pressure and purified bychromatography on silica, eluting with 50-100% ethyl acetate in hexane,to give the required product as a white foam (142 mg).

m/z 628 (M+H)⁺

3-[((1S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide

A solution of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]-5-[(phenylmethyl)oxy]benzamide(1.97 g, 3.77 mmol) and THF (70 mL) was evacuated and purged with Argon(×3). Palladium on carbon (10% w/w, 400 mg) was added and reactionmixture was evacuated and finally purged with hydrogen gas. Reactionmixture was left to stir at ambient temperature under hydrogen for 16hours. The palladium on carbon was filtered off and concentrated invacuo to give the product as a colourless oil (1.58 g, 97%).

¹H NMR δ (CDCl₃): 0.02 (s, 3H), 0.04 (s, 3H), 0.85 (s, 9H), 1.27 (d,3H), 1.53 (s, 3H), 1.55 (s, 3H), 3.63 (dd, 1H), 3.77 (dd, 1H), 4.41 (m,1H), 6.60 (s, 1H), 6.81 (s, 1H), 7.00 (s, 1H), 7.07 (s, 1H), 7.38 (s,1H), 8.78 (br. s, 1H); m/z 434 (M+H)⁺, 432 (M−H)⁻.

3-[((1S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]-5-[(phenylmethyl)oxy]benzamide

DIPEA (3.11 mL, 18.03 mmol) was added to a solution of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoicacid (3.00 g, 7.21 mmol), HATU (3.12 g, 8.21 mmol) and1-(1-methylethyl)-1H-pyrazol-3-amine (1.13 g, 9.01 mmol) in DMF (10 mL).The resulting mixture was stirred at ambient temperature for 16 hours.The DMF was removed in vacuo. The solvent was evaporated and the residuewas dissolved in 5% w/v citric acid (50 mL) and ethyl acetate (30 mL)and diethyl ether (30 mL) and the organic layer was further washed withsaturated aqueous sodium bicarbonate solution (30 mL) and brine (30 mL).The organic layer was separated, then dried (MgSO₄), filtered andevaporated. Purification by column chromatography, eluting with 1:4 to1:3 ethyl acetate:hexanes, afforded the title compound as a colourlessoil (2.40 g, 65%). ¹H NMR δ (CDCl₃): 0.01 (s, 3H), 0.03 (s, 3H), 0.86(s, 9H), 1.24 (d, 3H), 1.49 (s, 3H), 1.51 (s, 3H), 3.64 (dd, 1H), 3.78(dd, 1H), 4.39 (m, 1H), 4.46 (m, 1H), 5.09 (s, 2H), 6.70 (s, 1H), 6.78(s, 1H), 7.02 (s, 1H), 7.08 (s, 1H), 7.35 (m, 6H), 8.32 (br. s, 1H); m/z524 (M+H)⁺, 522 (M−H)⁻.

1-(1-Methylethyl)-1H-pyrazol-3-amine

2-Chloroacrylonitrile (3.41 mL, 42.59 mmol) was added at RT to astirring solution of N-isopropylhydrazine hydrochloride (4.71 g, 42.6mmol), potassium carbonate (11.8 g, 85.2 mmol) in water (50 mL). Thereaction was warmed to 45° C. for 4 hours before cooling back to RT. Theaqueous layer was then extracted with ethyl acetate (5×30 mL) and thecombined organic layers were dried (MgSO₄), treated with activatedcharcoal, filtered and evaporated. The residue was purified bychromatography, eluting with 67%-100% ethyl acetate in hexanes, toafford the title compound (3.08 g, 58%) as a 6:1 mixture of authenticproduct to regioisomeric product as an oil. The material was usedwithout further purification. ¹H NMR δ (CDCl₃): 1.42 (m, 6H), 3.58 (br.s, 2H), 4.25 (sept, 1H), 5.58 (d, 1H), 7.15 (d, 1H).

The preparation of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoicacid was described earlier.

EXAMPLE 243-{[5-(Azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide

A solution of 1,1-dimethylethyl3-{[(3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylate(157 mg, 0.4 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (95mg, 0.48 mmol) in acetonitrile (2 mL), containing potassium carbonate(111 mg, 0.8 mmol), was heated in a microwave reactor at 160° C. for 6hours. The reaction mixture was filtered and the filtrate evaporated todryness under reduced pressure and purified by chromatography on silica,eluting with 50-100% ethyl acetate in hexane to give a product which wasfurther purified by chromatography on silica, eluting with 0-8% methanolin ethyl acetate, to give the required product as a white foam (21 mg).

¹H NMR δ (CDCl₃): 1.25 (d, 3H), 2.30 (quin, 2H), 3.33 (s, 3H), 3.42-3.54(m, 2H), 4.12-4.29 (m, 4H), 4.54 (q, 1H), 6.77 (s, 1H), 6.81 (t, 1H),6.97 (d, 1H), 7.20 (s, 1H), 7.27 (s, 1H), 7.33 (d, 1H), 8.01 (d, 2H),8.28 (d, 1H), 10.27 (s, 1H); m/z 452 (M+H)⁺

The preparation of 1,1-dimethylethyl3-{[(3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylateis described below:

1,1-Dimethylethyl3-{[(3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylate

A solution of 1,1-dimethylethyl3-[({3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate(23 g, 47.8 mmol) in THF (140 mL) and ethanol (140 mL) was evacuated andpurged with nitrogen (×3). 10% Palladium on carbon (2.3 g; 10% w/w) wasadded and reaction mixture was evacuated and finally purged withhydrogen gas. The reaction mixture was left to stir at RT under ahydrogen balloon for 16 hours. The palladium on carbon was filteredthrough diatomaceous earth and the filtrate concentrated in vacuo togive a white foam (18 g, 97%).

¹H NMR δ (d₆-DMSO): 1.2 (d, 3H), 1.55 (s, 9H), 3.25 (s, 3H obscured bywater peak), 3.4-3.5 (m, 2H), 4.7 (m, 1H), 6.5 (s, 1H), 6.95 (d, 1H),7.0 (s, 1H), 7.1 (s, 1H), 8.2 (d, 1H), 9.65 (s, 1H), 11.2 (s, br, 1H);m/z 392 (M+H)⁺

1,1-Dimethylethyl3-[({3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate

DIPEA (28.5 mL, 164 mmol) was added to a suspension of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid(20.7 g, 65.6 mmol), HATU (31.2 g, 82.0 mmol) and 1,1-dimethylethyl3-amino-1H-pyrazole-1-carboxylate (15.0 g, 82.0 mmol) in DMF (30 mL) andthe reaction mixture stirred for 16 hours at RT. Water (250 mL) wasadded and the reaction mixture extracted with diethyl ether (3×150 mL).The organic layer was washed with saturated brine solution and dried(MgSO₄). The filtrate was concentrated in vacuo and the residuecrystallised on standing. The crystals were washed with isohexane togive to give the desired material as yellow crystals (23.4 g; 73%). m/z482 (M+H)⁺.

1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate

1H-Pyrazol-3-amine (428 mg, 5.15 mmol) was dissolved in DMF (5 mL) at 0°C. and treated with sodium hydride (206 mg, 5.15 mmol) followed bystirring for a further 30 min. Warmed di-tert-butyl dicarbonate (1.12 g,5.15 mmol) was then slowly added via syringe over 5 min and the reactionwas allowed to warm to room temperature and stirred for a further 2 h.The reaction was taken up in saturated aqueous sodium hydrogencarbonate(50 mL) and ethyl acetate (100 mL). The organic layer was separated thendried (MgSO₄), filtered and evaporated. Purification by columnchromatography (eluting with 1:1 ethyl acetate:hexanes to neat ethylacetate) afforded the title compound (117 mg) as a white solid. ¹H NMR δ(CDCl₃): 1.62 (s, 9H), 4.00 (br. s, 2H), 5.81 (d, 1H), 7.82 (d, 1H)1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate was also made byreacting a solution of 1H-pyrazol-3-amine in THF (1 g in approximately15.6 mL) with NaHMDS (2M in THF, 1.05 equivalents) then adding asolution of di-tert-butyl dicarbonate (1 equivalent) in THF(approximately 1 g of dicarbonate in 1.9 mL) and stirring at RT. Theresulting material was crystallised from a mixture of ethyl acetate andisohexane.

The preparation of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acidwas described earlier.

EXAMPLE 253-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

A mixture of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide(80 mg, 0.26 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (61mg, 0.26 mmol) and caesium carbonate (172 mg, 0.53 mmol) in acetonitrile(3 mL) was stirred in a Smith Creator microwave at 160° C. for 3 hours.The solvent was removed in vacuo and ethyl acetate (50 mL) added to theresidue. The organic phase was washed with water (20 mL), brine (50 mL),dried (MgSO₄), filtered and the solvent removed in vacuo to give ayellow oil which was chromatographed on silica, eluting with a gradientof 0-10% methanol in DCM, to give the title compound as a yellow foam(52 mg).

¹H NMR δ (CDCl₃): 2.16-2.24 (2H, m), 2.34-2.44 (4H, m), 3.78 (3H, s),3.89-4.01 (4H, m), 4.24 (2H, t), 4.37 (2H, t), 4.99 (1H, s), 6.80 (1H,s), 6.89 (1H, s), 7.23 (1H, s), 7.30 (2H, d), 8.16 (1H, s), 8.24 (1H,s), 8.73 (1H, s); m/z 498 (M+H)⁺.

The preparation of 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine wasdescribed earlier. The preparation of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamideis described below:

3-Hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

N-(1-Methyl-1H-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide(453 mg, 1.15 mmol) was dissolved in ethanol (5 mL) and ammonium formate(182 mg, 2.88 mmol) was added in one portion. The reaction was blanketedwith argon and 10% palladium on activated carbon (30 mg) was added. Thismixture was heated to 140° C. for 10 minutes in a Smith Creatormicrowave. The catalyst was filtered off and the volatiles removed invacuo to give the title product as a white solid (339 mg).

¹H NMR δ (CDCl₃): 2.06-2.14 (1H, m), 2.15-2.22 (1H, m), 3.72-3.73 (3H,s), 3.84-3.89 (1H, m), 3.92-3.98 (3H, m), 4.88 (1H, m), 6.53 (1H, t),6.78 (1H, d), 6.89 (1H, s), 6.95 (1H, s), 7.28 (1H, d), 9.27 (1H, s);m/z 304 (M+H)⁺.

N-(1-Methyl-1H-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

A suspension of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(450 mg, 1.39 mmol), (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate(507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) inacetonitrile (5 mL) was stirred in a Smith Creator microwave at 160° C.for 3 hours. The solvent was removed in vacuo and ethyl acetate added.The organics were washed with water (40 mL), brine (40 mL), dried(MgSO₄), filtered and the solvent removed in vacuo to give a yellow foamwhich was chromatographed on silica, eluting with a gradient of 0-100%ethyl acetate in iso-hexane, to give the title compound as a white foam(452 mg).

¹H NMR δ (CDCl₃): 2.09-2.14 (1H, m), 2.14-2.24 (1H, m), 3.68 (3H, s),3.86-3.91 (1H, m), 3.94-3.98 (3H, m), 4.89 (1H, s), 5.03 (2H, s), 6.64(1H, t), 6.85 (1H, s), 6.96 (1H, d), 7.07 (1H, t), 7.27 (1H, m),7.33-7.41 (5H, m), 9.31 (1H, s); m/z 394 (M+H)⁺.

(3R)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate

4-Toluene sulfonyl chloride (1.65 g, 8.63 mmol) was added to a solutionof R-3-hydroxytetrahydrofuran (0.8 g, 9.08 mmol) and pyridine (0.88 mL,10.9 mmol) in DCM (15 mL). The reaction was stirred at RT for 72 hours.Water (10 mL) and 1M hydrochloric acid (1 mL) were added and the mixtureextracted with DCM (15 mL). The organic layer was washed with brine (20mL), dried (MgSO₄), filtered and reduced in vacuo to give a yellow oilwhich was chromatographed on silica, eluting with a gradient of 0-50%ethyl acetate in isohexane, to give the desired compound (1.0 g). ¹H NMRδ (CDCl₃): 2.13 (m, 2H), 2.47 (s, 3H), 3.80-3.95 (m, 4H), 5.15 (m, 1H),7.37 (d, 2H), 7.81 (d, 2H).

3-Hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide

A suspension ofN-(1-methyl-1H-pyrazol-3-yl)-3,5-bis[(phenylmethyl)oxy]benzamide (1.0 g,2.42 mmol) was dissolved in ethanol (12 mL) and ammonium formate (229mg, 3.63 mmol) was added in one portion. The reaction was blanketed withargon and 10% palladium on activated carbon (10 mg) was added. Thismixture was heated to 140° C. for 5 minutes in a Smith Creatormicrowave. The catalyst was filtered off and the volatiles removed invacuo, the residue was chromatographed on silica, eluting with agradient of 30-100% ethyl acetate in iso-hexane, to give the titlecompound as a white solid (378 mg).

¹H NMR δ (d₆-DMSO): 3.78 (3H, s), 5.13 (2H, s), 6.55-6.57 (2H, m), 6.99(1H, s), 7.17 (1H, s), 7.34-7.48 (5H, m), 7.60 (1H, d), 9.74 (1H, s),10.70 (1H, s); m/z 324 (M+H)⁺.

N-(1-Methyl-1H-pyrazol-3-yl)-3,5-bis[(phenylmethyl)oxy]benzamide

Oxalyl chloride (7.71 mL, 89.7 mmol) was added dropwise to a suspensionof 3,5-dibenzyloxybenzoic acid (20.0 g, 59.8 mmol) in DCM (0.5 L) underargon. The reaction was stirred at RT for 6 hours after which time thevolatiles were removed in vacuo. The residue was taken up in DCM (300mL) and a solution of 1-methyl-1H-pyrazol-3-amine (5.81 g, 59.8 mmol) inDCM (50 mL) was added dropwise. The resulting solution was stirred for16 hours at RT after which time a precipitate had formed. The solid wasisolated by filtration and recrystallised from ethanol to give the titlecompound as a white solid (14.8 g). ¹H NMR δ (d₆-DMSO): 3.84 (3H, s),5.17 (4H, s), 6.59 (1H, d), 6.84 (1H, t), 7.33-7.46 (12H, m), 7.62 (1H,d), 10.83 (1H, s); m/z 414 (M+H)⁺.

EXAMPLE 263-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

A mixture of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide(80 mg, 0.26 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (64 mg,0.26 mmol), bromotris(triphenylphosphine)copper(I) (49 mg, 0.05 mmol)and caesium carbonate (257 mg, 0.78 mmol) in acetonitrile (3 mL) wasstirred in a Smith Creator microwave at 160° C. for 6 hours. The solidwas filtered off and the solvent was removed in vacuo and ethyl acetate(50 mL) added to the residue. The organic phase was washed with water(20 mL), brine (50 mL), dried (MgSO₄), filtered and the solvent removedin vacuo to give a yellow oil which was chromatographed on silica,eluting with a gradient of 0-10% methanol in DCM, to give the titlecompound as a colourless solid (58 mg). This compound was crystallisedfrom ethyl acetate and isohexane using vapour diffusion techniques. ¹HNMR δ (CDCl₃): 2.11-2.17 (1H, m), 2.20-2.29 (1H, m), 2.32-2.39 (2H, m),3.78 (3H, s), 3.88-3.93 (1H, m), 3.96-4.02 (3H, m), 4.25 (2H, t), 4.71(2H, t), 4.97 (1H, t), 6.73 (1H, t), 6.79 (1H, s), 7.11 (1H, s), 7.22(1H, s), 7.27-7.30 (1H, m), 7.36-7.39 (1H, m), 8.12 (1H, d), 8.32 (1H,d), 8.73 (1H, s); m/z 464 (M+H)⁺.

The preparation of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamideand 2-(azetidin-1-ylcarbonyl)-5-bromopyridine was described earlier.

EXAMPLE 273-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

A mixture of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide(80 mg, 0.26 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (52 mg,0.26 mmol) and caesium carbonate (172 mg, 0.53 mmol) in acetonitrile (3mL) was stirred in a Smith Creator microwave at 160° C. for 1 hr. Thesolvent was removed in vacuo and ethyl acetate (50 mL) added to theresidue. The organic phase was washed with water (20 mL), brine (50 mL),dried (MgSO₄), filtered and the solvent removed in vacuo to give ayellow oil which was chromatographed on silica eluting with a gradientof 0-10% methanol in DCM to give the title compound (36 mg, 31%) as awhite foam. This compound was crystallised from ethyl acetate andisohexane using vapour diffusion techniques. ¹H NMR δ (CDCl₃): 2.12-2.19(1H, m), 2.21-2.28 (1H, m), 2.34-2.42 (2H, m), 3.75 (3H, s), 3.88-3.93(1H, m), 3.98-4.02 (3H, m), 4.23 (2H, t), 4.69 (2H, t), 4.95-4.97 (1H,m), 6.80 (1H, d), 6.87 (1H, t), 7.23 (1H, d), 7.27-7.30 (1H, m),7.28-7.30 (1H, m), 8.34 (1H, d), 8.84 (1H, d), 8.98 (1H, s); m/z 465(M+H)⁺.

The preparation of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(38)-tetrahydrofuran-3-yloxy]benzamidewas described earlier.

The preparation of 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine isdescribed below:

2-(Azetidin-1-ylcarbonyl)-5-chloropyrazine

Oxalyl chloride (1.55 mL, 17.48 mmol), followed by DMF (2 drops), wasadded to a mixture of 5-chloropyrazine-2-carboxylic acid (2.31 g, 14.57mmol) in DCM (40 mL). The reaction was stirred at RT for 2 hours afterwhich time the volatiles were removed in vacuo. The residue was taken upDCM (40 mL) and azetidine (1.08 mL, 16.03 mmol) and triethylamine (4.46mL, 32.06 mmol) added. The mixture was stirred at RT for 72 hours. Thevolatiles were removed in vacuo and ethyl acetate (100 mL) added to theresidue. The organics were washed with water (100 mL), citric acid (50mL), saturated sodium bicarbonate solution (50 mL), brine (50 mL), dried(MgSO₄), filtered and the solvent removed in vacuo to give a yellowsolid. The residue was chromatographed on silica, eluting with agradient of 50-100% ethyl acetate in iso-hexane, to give the desiredcompound as a yellow solid (2.38 g). ¹H NMR δ (CDCl₃): 2.35-2.42 (2H,m), 4.26 (2H, t), 4.67 (2H, t), 8.52 (1H, d), 9.09 (1H, d); m/z 198(M+H)⁺.

5-Chloropyrazine-2-carboxylic acid

To a solution of methyl-5-chloropyrazine-2-carboxylate (120 mg, 0.70mmol) in a mixture of acetonitrile (2 mL) and DMF (1 mL) was addedlithium chloride (295 mg, 6.95 mmol). The suspension was heated to 160°C. for 5 mins in a Smith creator microwave after which time the reactionwas diluted with water (10 mL). Saturated sodium bicarbonate solution(20 mL) was added and the aqueous layered extracted twice with ethylacetate (30 mL). The combined organics were discarded and the aqueouslayer adjusted to pH 4 with 1N hydrochloric acid. The aqueous phase wasextracted twice with ethyl acetate (20 mL) and the combined organicswashed with water (2×20 mL), brine (10 mL) and dried (MgSO₄). Thevolatiles were removed to give the title compound as a colourless solid(68 mg).

¹H NMR δ (CDCl₃): 7.20 (1H, br s), 8.72 (1H, s), 9.21-9.21 (1H, m); m/z157 (M−H)⁺.

EXAMPLE 283-{[4-(Azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Cesium carbonate (488 mg, 1.5 mmol) was added to a solution of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide(153 mg, 0.5 mmol) and 4-(azetidin-1-ylcarbonyl)-2-bromo-1,3-thiazole(206 mg, 0.75 mmol) in acetonitrile (5 mL) and the stirred mixtureheated at 150° C. in a Biotage Initiator Microwave apparatus for 8hours. The mixture was cooled to RT and pressure, poured onto water (75mL) and extracted with ethyl acetate (3×25 mL). The combined organiclayers were washed with brine, dried (MgSO₄) and evaporated to a residuewhich was chromatographed on silica, eluting with ethyl acetate, to givethe desired material (95 mg).

¹H NMR δ (CDCl₃): 1.3 (d, 3H), 2.2 (m, 2H), 3.3 (s, 3H), 3.4-3.55 (m,2H), 3.7 (s, 3H), 4.1 (t, 2H), 4.4 (t, 2H), 4.5 (m, 1H), 6.7 (s, 1H),6.95 (s, 1H), 7.25 (s, 1H), 7.3 (s, 2H), 7.35 (s, 1H), 7.65 (s, 1H) and8.8 (s, 1H); m/z 472 (M+H)⁺.

The following compound was prepared in an analogous fashion from4-(azetidin-1-ylcarbonyl)-2-bromo-1,3-thiazole and3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide

Example Structure m/z NMR 28a

442(M + H)⁺ ¹H NMR δ (CDCl₃): 1.3 (d, 6 H), 2.2 (m, 2 H)3.7 (s, 3 H),4.1 (m, 2 H), 4.4 (m, 2 H), 4.5 (m,1 H), 6.7 (s, 1 H), 6.9 (s, 1 H),7.25 (d, 2 H), 7.3(s, 1 H), 7.65 (s, 1 H) and 9.0 (s, 1 H).

The preparation of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamidewas described earlier

The preparation of 4-(azetidin-1-ylcarbonyl)-2-bromo-1,3-thiazole isdescribed below:

4-(Azetidin-1-ylcarbonyl)-2-bromo-1,3-thiazole

To a solution of 2-bromothiazole-5-carboxylic acid (752 mg, 3.62 mmol)in DCM (10 mL) was slowly added oxalyl chloride (0.38 mL, 4.34 mmol) andthen DMF (1 drop). The mixture was stirred for 4 hours, following whichthe organics were removed in vacuo, and the residues azeotroped withtoluene (10 mL). The crude material was dissolved in DCM (10 mL) andslowly added to a stirred suspension of azetidine hydrochloride (404 mg,4.34 mmol) and triethylamine (1.8 mL, 13 mmol) in DCM (25 mL). Themixture was stirred at RT for 2 hours before the organics were removedin vacuo. The residue was partitioned between ethyl acetate (50 mL) andwater (25 mL), the organic layer washed with brine (25 mL), dried(MgSO₄) and evaporated to a residue which was chromatographed on silica,eluting with 40% ethyl acetate in iso-hexane, to give the desiredcompound (500 mg).

¹H NMR δ (CDCl₃): 2.3 (m, 2H), 4.15 (m, 2H), 4.6 (m, 2H) and 8.0 (s,1H); m/z 249 (M+H)⁺.

EXAMPLE 293-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A solution of5-[(3-{[(is)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid (12 mg, 0.03 mmol), azetidine hydrochloride (4 mg, 0.06 mmol), HATU(14 mg, 0.04 mmol) and DIPEA (0.02 mL, 0.11 mmol) in DMF (1 mL) wasstirred at RT over the weekend. Water (15 mL) was added and the solutionextracted with ethyl acetate (25 mL). The ethyl acetate layer was washedwith brine (20 mL), dried (MgSO₄), and evaporated to a residue which waschromatographed by preparative HPLC on C18 reversed phase, eluting with5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA), to give therequired product along with 15% of a co-eluting impurity (5 mg). ¹H NMRδ (CDCl₃): 0.92 (t, 3H), 0.97 (t, 0.45H), 1.69 (quin, 2H), 1.76 (m,0.3H), 2.34 (quin, 2H), 3.76 (m, 2H), 3.86 (s, 3H), 4.23 (t, 2H), 4.49(sextet, 1H), 4.66 (t, 2H), 4.77 (m, 0.15H), 6.93 (t, 1H), 6.99 (d, 1H),7.34 (s, 1H), 7.46 (s, 1H), 7.50 (s, 1H), 8.29 (s, 1H), 8.78 (s, 1H),10.68 (s, 1H), 10.78 (s, 0.15H); m/z 468 (M+H)⁺

The spectroscopic data is consistent with 15% of the following impurity3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(2S)-2-hydroxybutyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide.

The preparation of5-[(3-{[(1S)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid is described below:

5-[(3-{[(1S)-1-(Hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyloxy]pyrazine-2-carboxylic acid

Lithium hydroxide monohydrate (6 mg, 0.14 mmol) in water (1 mL) wasadded to a solution of methyl5-[(3-{[(1S)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate(25 mg, 0.06 mmol) in THF (1 mL). The mixture was allowed to stir at RTfor 16 hours. The THF was removed in vacuo and the resulting solutionwas partitioned between water (10 mL) and ethyl acetate (25 mL), theethyl acetate layer was washed with brine (10 mL) and dried (MgSO₄). Theaqueous layer was then adjusted to pH 7 by addition of 1M hydrochloricacid and extracted with ethyl acetate (25 mL). The ethyl acetate layerwas washed with brine (10 mL) and dried (MgSO₄). The ethyl acetateextracts were combined and evaporated to give the required product (12mg). m/z 428.44 (M+H)⁺

Methyl5-[(3-{[(1S)-1-(hydroxymethyl)propyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate

Methyl 5-chloropyrazine-2-carboxylate (104 mg, 0.60 mmol) and cesiumcarbonate (467 mg, 1.43 mmol) were added to a solution of3-hydroxy-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(175 mg, 0.570 mmol), in acetonitrile (5 mL) and the mixture heated in amicrowave reactor at 160° C. for 330 minutes. The acetonitrile wasremoved in vacuo and the residue dissolved in ethyl acetate (25 mL),washed with water (20 mL), brine (20 mL), dried (MgSO₄) and evaporatedto a residue which was chromatographed by preparative HPLC on C18reversed phase, eluting with 5-95% acetonitrile (+0.2% TFA) in water(+0.2% TFA), to give the required product (41 mg). ¹H NMR δ (CDCl₃):0.97 (t, 3H), 1.78 (quin, 2H), 3.82 (s, 3H), 3.91 (s, 3H), 4.52 (m, 3H),4.66 (quin, 1H), 6.59 (t, 1H), 6.89 (d, 1H), 7.05 (t, 1H), 7.15 (t, 1H),8.19 (d, 1H), 8.79 (d, 1H), 9.86 (s, 1H); m/z 442 (M+H)⁺

3-Hydroxy-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

To a solution of3-hydroxy-5-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide(500 mg, 1.6 mmol) in acetonitrile (25 mL), iodotrimethylsilane (1.11mL, 7.8 mmol) was added and the resulting mixture stirred for 16 hours.Saturated sodium hydrogencarbonate solution (10 mL) was added, thesolution stirred for 10 mins, saturated aqueous sodium thiosulfate (5mL) was added then the acetonitrile was removed in vacuo. The residualaqueous layer was extracted with ethyl acetate (3×40 mL) and the organiclayers combined, dried (MgSO₄), filtered and evaporated and purified bycolumn chromatography, eluting with 85% ethyl acetate in isohexane, togive the title compound as a colourless foam (405 mg). ¹H NMR δ(d₆-DMSO): 0.95 (t, 3H), 1.5-1.8 (m, 2H), 3.5 (m, 2H), 3.8 (s, 3H), 4.3(m, 1H), 4.8 (t, 1H), 6.45 (s, 1H), 6.55 (s, 1H), 6.9 (s, 1H), 7.05 (s,1H), 7.55 (s, 1H), 9.6 (s, 1H); m/z 306 (M+H)⁺

3-Hydroxy-5-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

To a solution of3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(4.6 g, 11 mmol) in 1:1 THF:methanol (100 mL) was added 10% w/wpalladium on carbon (450 mg) and the resulting mixture was stirred underan atmosphere of hydrogen for 6 hours. The atmosphere was replaced withargon and the mixture was filtered and evaporated to afford the titlecompound as a white solid (3.6 g).

¹H NMR δ (CDCl₃): 0.95 (t, 3H), 1.7 (m, 2H), 3.4 (s, 3H), 3.55 (m, 2H),3.8 (s, 3H), 4.3 (m, 1H), 6.65 (s, 1H), 6.8 (s, 1H), 7.0 (m, 2H), 7.2(m, 1H), 7.3 (s, 1H), 8.7 (s, 1H); m/z 320 (M+H)⁺

3-({(1S)-1-[(Methyloxy)methyl]propyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide

To a solution of3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-5-[(phenylmethyl)oxy]benzoicacid (4.75 g, 14.4 mmol) and 3-amino-1-methyl-1H-pyrazole (2.04 g, 21mmol) in DMF (25 mL) was added HATU (8.53 g, 22.4 mmol) then DIPEA (7.0mL, 40 mmol) and the resulting mixture was stirred for 16 hours. Themixture was partitioned between ethyl acetate (100 mL) and water (30mL). The organic layer was separated, washed with 1N citric acid (30mL), water (30 mL), saturated sodium bicarbonate (30 mL), water (30 mL)and brine (30 mL) then dried (MgSO₄) and evaporated. The residue waspurified by column chromatography, eluting with 50% ethyl acetate inisohexane, to give the title compound as a colourless oil (4.57 g).

¹H NMR δ (CDCl₃): 0.95 (t, 3H), 1.7 (m, 2H), 3.4 (s, 3H), 3.55 (m, 2H),3.8 (s, 3H), 4.3 (m, 1H), 5.05 (s, 2H), 6.75 (s, 1H), 6.8 (s, 1H), 7.05(d, 2H), 7.25 (s, 1H), 7.4 (m, 5H), 8.45 (s, 1H); m/z 410 (M+H)⁺

3-({(1S)-1-[(Methyloxy)methyl]propyl}oxy)-5-[(phenylmethyl)oxy]benzoicacid

To a solution of methyl3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-5-[(phenylmethyl)oxy]benzoate(6.85 g, 20 mmol) in 3:1 THF:methanol (100 mL) was added 1N lithiumhydroxide solution in water (40 mL, 40 mmol), then a further 100 mLwater was added portionwise at intervals while the resulting mixture wasstirred for 2 hours. The organic solvents were removed by evaporationand the cloudy solution filtered. The pH of the filtrate was adjusted to3 by the addition of 2 M hydrochloric acid. This was extracted withethyl acetate (3×70 mL). The combined organic extracts were dried(MgSO₄) and evaporated to afford the title compound as a colourless oilwhich solidified (6.36 g,).

¹H NMR δ (CDCl₃): 0.95 (t, 3H), 1.7 (m, 2H), 3.4 (s, 3H), 3.55 (m, 2H),4.3 (m, 1H), 5.05 (s, 2H), 6.8 (s, 1H), 7.3-7.5 (m, 7H); m/z 329 (M−H)⁻

Methyl3-({(1S)-1-[(methyloxy)methyl]propyl}oxy)-5-[(phenylmethyl)oxy]benzoate

A stirred solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate(7.5 g, 29 mmol), (R)-1-methoxy-butan-2-ol (3.76 g, 36.25 mmol) andtriphenylphosphine (9.5 g, 36.25 mmol) in dry THF (75 mL) was cooled inan ice-bath and a solution of 40% DEAD in toluene (15.8 mL, 36.25 mmol)was added dropwise over 30 minutes. The reaction mixture was allowed towarm slowly to 10° C. and stirred for 16 hours. The THF was evaporatedand the residue was dissolved in 30% ethyl acetate in isohexane andcooled in ice. The resultant precipitate was removed by filtration andwashed with 10% ethyl acetate in isohexane. The filtrate was evaporatedand purified by column chromatography, eluting with 10% ethyl acetate inisohexane, to give the title compound as a colourless oil (6.85 g).

¹H NMR δ (CDCl₃): 0.95 (t, 3H), 1.7 (m, 2H), 3.35 (s, 3H), 3.55 (m, 2H),3.9 (s, 3H), 4.3 (m, 1H), 5.05 (s, 2H), 6.8 (s, 1H), 7.25 (m, 2H), 7.4(m, 5H); m/z 345 (M+H)⁺

The preparation of (R)-1-methoxy-butan-2-ol was described in theliterature [Coke, J. L.; Shue, R. S., J. Org. Chem. 38, (1973),2210-2211].

The preparation of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate wasdescribed earlier.

EXAMPLE 303-{[2-(Azetidin-1-ylcarbonyl)pyrimidin-5-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1,3-thiazol-2-ylbenzamide

A mixture of3-hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-1,3-thiazol-2-ylbenzamide(130 mg, 0.42 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyrimidine (113mg, 0.46 mmol), cesium carbonate (412 mg, 1.26 mmol) andbromotris(triphenylphosphine)copper(I) (118 mg, 0.13 mmol) in DMA (5 mL)was stirred in the a microwave reactor at 160° C. for 4 hours. Ethylacetate (50 mL) was added to the residue and the organics washed withwater (20 mL), brine (50 mL), dried (MgSO₄), filtered and the solventremoved in vacuo to give a brown oil. The residue was chromatographed onsilica, eluting with a gradient of 0-10% methanol in ethyl acetate, togive the desired compound (67 mg). ¹H NMR δ (CDCl₃): 1.34 (d, 3H), 2.38(quintet, 2H), 3.40 (s, 3H), 3.49-3.61 (m, 2H), 4.29 (t, 2H), 4.59-4.67(m, 3H), 6.92 (t, 1H), 6.98 (d, 1H), 7.23 (d, 1H), 7.44 (t, 1H), 7.49(t, 1H), 8.54 (s, 2H), 11.96 (s, 1H); m/z 470 (M+H)⁺

The preparation of3-hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-1,3-thiazol-2-ylbenzamidewas described earlier.

The preparation of 2-(azetidin-1-ylcarbonyl)-5-bromopyrimidine isdescribed below:

2-(Azetidin-1-ylcarbonyl)-5-bromopyrimidine

Oxalyl chloride (1.50 mL, 16.79 mmol), followed by DMF (2 drops), wereadded to a mixture of 5-bromopyrimidine-2-carboxylic acid (2.86 g, 14.0mmol) in DCM (40 mL). The reaction was stirred at RT for 2 hours, thevolatiles removed in vacuo and the residue dissolved in DCM (40 mL).Azetidine hydrochloride (1.44 g, 15.39 mmol), followed by triethylamine(4.29 mL, 30.78 mmol), were added and the mixture stirred at RT for 72hours. The mixture was concentrated in vacuo and ethyl acetate (100 mL)added to the residue. The organics were washed with water (100 mL),citric acid (50 mL), saturated sodium bicarbonate solution (50 mL),brine (50 mL), dried (MgSO₄), filtered and the solvent removed in vacuoto give a yellow solid. The solid was chromatographed on silica, elutingwith a gradient of 50-100% ethyl acetate in isohexane, to give thedesired compound as a yellow solid (0.86 g).

The preparation of 5-bromopyrimidine-2-carboxylic acid is described inthe literature (International Patent Application WO 2005/028452).

EXAMPLE 313-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-(cyclopentyloxy)-N-(o-methyl-1H-pyrazol-3-yl)benzamide

3-(Cyclopentyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamidae (200mg, 0.67 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (159 mg, 0.80mmol) and potassium carbonate (184 mg, 1.33 mmol) weredissolved/suspended in acetonitrile (3.5 mL). The reaction mixture washeated for 4 hours at 120° C. in a microwave reactor. The mixture wascooled, filtered and concentrated in vacuo. The crude product waschromatographed on silica, eluting with 0-5% methanol in DCM, to givethe required product as a white foam (282 mg).

¹H NMR δ (d₆-DMSO): 1.61 (m, 2H), 1.74 (m, 4H), 1.94 (m, 2H), 2.30 (m,2H), 3.78 (s, 3H), 4.10 (t, 2H), 4.57 (t, 2H), 4.94 (m, 1H), 6.57 (d,1H), 7.01 (t, 1H), 7.42 (m, 1H), 7.47 (m, 1H), 7.60 (d, 1H), 8.55 (d,1H), 8.68 (d, 1H), 10.80 (s, 1H). m/z 463 (M+H)⁺

The following compound was made in an analogus fashion from3-(cyclopentyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide and5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine.

Example Structure m/z ¹H NMR (d₆-DMSO) 31a

496(M + H)⁺ δ: 1.69 (m, 2 H), 1.82 (m, 4 H), 2.03 (m, 2 H)2.34 (m, 2 H),3.99 (s, 3 H), 4.14 (t, 2 H), 4.45(t, 2 H), 5.03 (m, 1 H), 6.65 (d, 1H), 7.06 (t,1 H), 7.47 (t, 1 H), 7.54 (t, 1 H), 7.68 (d, 1 H),8.30 (d, 1H), 8.42 (d, 1 H), 10.87 (s, 1 H).

The preparations of 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine and5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine were described earlier.

The preparation of3-(cyclopentyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide isdescribed below:

3-(Cyclopentyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide

3-(Cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(1.87 g, 4.78 mmol) was dissolved in ethanol (40 mL) and 10% palladiumon charcoal (102 mg) catalyst added under argon. The reaction wasstirred under an atmosphere of hydrogen for 86 hours, then filteredthrough Celite® and concentrated in vacuo to a light brown solid (1.31g). ¹H NMR (d₆-DMSO): 1.54 (m, 2H), 1.76 (m, 4H), 1.96 (m, 2H), 2.75 (s,1H), 3.83 (s, 3H), 4.91 (m, 1H), 6.49 (m, 1H), 6.61 (m, 1H), 6.98 (m,1H), 7.06 (m, 1H), 7.65 (s, 1H), 9.73 (br s, 1H); m/z 302 (M+H)⁺

3-(Cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide

3-(Cyclopentyloxy)-5-[(phenylmethyl)oxy]benzoic acid (3.14 g, 10.0mmol), 1-methyl-1H-pyrazol-3-amine (1.95 g, 20 mmol) and HATU (4.95 g,13 mmol) were dissolved in DMF (12.5 mL) then DIPEA (3.49 mL, 20 mmol)was added. The resultant mixture was stirred at RT for 20 hours. Themixture was quenched with water (150 mL) and extracted with ethylacetate (2×75 mL), washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo to leave a yellow oil. The residue waschromatographed on silica, eluting with 0-30% ethyl acetate inisohexane, to give the desired product as a clear gum (1.87 g).

¹H NMR δ (CDCl₃): 1.59 (m, 4H), 1.83 (m, 4H), 3.79 (s, 3H), 4.76 (m,1H), 5.08 (s, 2H), 6.66 (t, 1H), 6.82 (m, 1H), 7.01 (m, 1H), 7.08 (m,1H), 7.26 (m, 1H), 7.33 (m, 1H), 7.35-7.45 (m, 4H), 8.67 (s, 1H); m/z392 (M+H)⁺

3-(Cyclopentyloxy)-5-[(phenylmethyl)oxy]benzoic acid

Methyl 3-(cyclopentyloxy)-5-[(phenylmethyl)oxy]benzoate (9.25 g, 28.34mmol) was dissolved in THF (120 mL) and a solution of lithium hydroxidemono hydrate (3.49 g, 85.0 mmol) in water (60 mL) added. The bi-phasicsolution was stirred at RT for 16 hours (LCMS indicated reaction 80%complete), methanol (15 mL) added and the mixture stirred for a further4 hours. The THF was removed in vacuo then water (40 mL) added and thepH adjusted to 7 with hydrochloric acid. The solid was collected andwashed thoroughly with cold water (8.85 g).

¹H NMR δ (d₆-DMSO): 1.64 (m, 2H), 1.76 (m, 4H), 1.96 (m, 2H), 4.89 (m,1H), 5.19 (s, 2H), 6.80 (s, 1H), 7.07 (s, 1H), 7.16 (s, 1H), 7.34-7.53(m, 5H); m/z 311 (M+H)⁺

Methyl 3-(cyclopentyloxy)-5-[(phenylmethyl)oxy]benzoate

Methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (10 g, 38.7 mmol),1-cyclopentanol (6.135 mL, 58.07 mmol) and triphenylphosphine (15.24 g,58.07 mmol) were stirred under argon in THF (166 mL) and cooled in anice bath to 5° C. DEAD (25.3 mL, 58.1 mmol) was added dropwise to themixture, maintaining the internal temperature in the range 5-10° C.Stirring was continued for 16 hours. The mixture was concentrated invacuo, re-dissolved in ethyl acetate (60 mL) and isohexane (60 mL), theresultant precipitate removed and the solution concentrated in vacuo togive a yellow oil. The residue was chromatographed on silica, elutingwith 0-30% ethyl acetate in isohexane, to give a colourless oil whichcrystallised to a white solid under vacuum.

¹H NMR δ (CDCl₃): 1.62 (m, 2H), 1.71-1.98 (m, 6H), 3.90 (s, 3H), 4.76(m, 1H), 5.08 (s, 2H), 6.69 (m, 1H), 7.16 (m, 1H), 7.23 (m, 1H),7.29-7.44 (m, 5H); m/z 325 (M+H)⁺

The preparation of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate wasdescribed earlier.

EXAMPLE 323-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-(cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide

3-(Cyclopentyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200mg, 0.67 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (193 mg, 0.80mmol), bromotris(triphenylphosphine)copper (186 mg, 0.2 mmol) andcaesium carbonate (230 mg, 0.70 mmol) were dissolved/suspended in DMA(3.5 mL). The reaction mixture was heated for 40 mins at 200° C. in amicrowave reactor then allowed to cool, filtered and reduced in vacuo.The crude product was purified by chromatography on silica, eluting with0-100% ethyl acetate in isohexane, to give the desired compound as aslightly yellow foam (176 mg). ¹H NMR δ (d₆-DMSO): 1.61 (m, 2H), 1.73(m, 4H), 1.94 (m, 2H), 2.28 (m, 2H), 3.78 (s, 3H), 4.08 (t, 2H), 4.59(t, 2H), 4.95 (m, 1H), 6.56 (d, 1H), 6.88 (t, 1H), 7.28 (m, 1H), 7.43(t, 1H), 7.56 (m, 1H), 7.59 (d, 1H), 7.99 (d, 1H), 8.41 (m, 1H), 10.85(s, 1H); m/z 462 (M+H)⁺

EXAMPLE 333-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(1:1)

DIPEA (0.26 mL, 1.5 mmol) was added to a mixture of5-[(3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid and5-[(3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid (1:1) (0.16 g, 0.37 mmol), azetidine hydrochloride (71 mg, 0.75mmol) and HATU (299 mg, 0.79 mmol) in DMF (5 mL) and stirred at RT for72 hours. Ethyl acetate (40 mL) was added and the mixture washed withwater (2×30 mL), brine (30 mL), dried (MgSO₄), filtered and reduced invacuo to give a yellow oil which was chromatographed on silica, elutingwith 0-100% ethyl acetate in isohexane to give the titled mixture ofdiasteroisomers as a colourless oil. The mixture was separated by chiralpreparatory HPLC on a Chiralpak IA (250 mm×20 mm) EG014 column, elutingwith 30% ethanol in tertbutylmethyl ether. The first diastereomereluted, Example 33a, was isolated as a white foam (18 mg).

¹H NMR δ (CDCl₃): 1.19 (d, 3H), 1.23 (d, 3H), 2.26-2.34 (m, 3H), 3.74(s, 3H), 3.77-3.85 (m, 1H), 4.13-4.23 (m, 3H), 4.63 (t, 2H), 6.72 (d,1H), 6.86 (t, 1H), 7.16-7.22 (m, 2H), 7.27-7.30 (m, 1H), 8.27 (d, 1H),8.31 (s, 1H), 8.79 (d, 1H); m/z 467 (M+H)⁺

The second diastereomer eluted, Example 33b, was isolated as a whitefoam (19 mg).

¹H NMR δ (CDCl₃): 1.19 (d, 3H), 1.22 (d, 3H), 2.27-2.36 (m, 3H), 3.73(s, 3H), 3.76-3.84 (m, 1H), 4.13-4.22 (m, 3H), 4.62 (t, 2H), 6.72 (d,1H), 6.86 (t, 1H), 7.17-7.19 (m, 1H), 7.21 (d, 1H), 7.28 (t, 1H), 8.26(d, 1H), 8.40 (s, 1H), 8.79 (d, 1H); m/z 467 (M+H)⁺

The preparation of a mixture of5-[(3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid and5[(3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid (1:1) is described below:

5-[(3-{[(1R,2R)-2-Hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid and5-[(3-r{[(1S,2S)-2-Hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylicacid (1:1)

Lithium hydroxide monohydrate (38 mg, 0.88 mmol) in water (3 mL) wasadded to methyl5-[(3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylateand methyl5-[(3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate(1:1) (0.26 g, 0.59 mmol) in THF (6 mL) and the mixture stirred at RTfor 72 hours. The THF was removed in vacuo and the aqueous residueadjusted to pH3 with citric acid, then extracted into ethyl acetate,washed with water (30 mL), brine (30 mL), dried (MgSO₄), filtered andthe solvent removed in vacuo to give the desired compound as a whitesolid (0.16 g).

¹H NMR δ (d₆-DMSO): 1.16 (d, 3H), 1.26 (d, 3H), 3.84 (s, 3H), 4.20 (m,1H), 4.49 (m, 1H), 4.89 (d, 1H), 6.64 (d, 1H), 7.13 (t, 1H), 7.49 (s,1H), 7.59 (s, 1H), 7.67 (d, 1H), 8.72 (d, 1H), 8.85 (d, 1H), 10.93 (s,1H), 13.53 (s, 1H); m/z 426 (M−H)⁻

Methyl5-[(3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylateand Methyl5-[(3-{[(1S,2S-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate(1:1)

A mixture of3-hydroxy-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-hydroxy-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(1:1) (230 mg, 0.75 mmol), methyl 5-chloropyrazine-2-carboxylate (195mg, 1.13 mmol) and potassium carbonate (208 mg, 1.51 mmol) inacetonitrile (5 mL) was stirred in a microwave reactor at 130° C. for 3hours. The solvent was removed in vacuo and water added. The mixture wasacidified, extracted into ethyl acetate and the combined organics washedwith brine, dried (MgSO₄), filtered and reduced in vacuo to give ayellow foam (265 mg), which was used in the next step without furtherpurification. ¹H NMR δ (CDCl₃): 1.29 (m, 6H), 1.99 (s, 1H), 3.80 (s,3H), 3.90 (quintet, 1H), 4.05 (s, 3H), 4.25 (quintet, 1H), 6.82 (d, 1H),6.95 (t, 1H), 7.30 (m, 2H), 7.39 (s, 1H), 8.55 (s, 1H), 8.55 (s, 1H),8.86 (s, 1H); m/z 442 (M+H)⁺

The preparation of3-hydroxy-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamideand3-hydroxy-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide(1:1) was described earlier.

EXAMPLE 343-{[5-(Azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide(159 mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole(152 mg, 0.75 mmol) in acetonitrile (5 mL) and the stirred mixtureheated at 120° C. in a microwave reactor for 1 hour. The mixture wascooled to RT and ambient pressure, the acetonitrile evaporated in vacuo,the residue partitioned between water (25 mL) and ethyl acetate (50 mL),the organic layer washed with brine, dried (MgSO₄) and evaporated to aresidue which was chromatographed on silica, eluting with ethyl acetate,to give the desired product (181 mg).

¹H NMR δ (CDCl₃): 1.3 (d, 3H), 2.35 (m, 2H), 2.5 (s, 3H), 3.3 (s, 3H),3.45-3.55 (m, 2H), 4.1-4.4 (m, 4H), 4.55 (m, 1H), 7.0 (d, 1H), 7.35 (d,1H), 7.45 (s, 1H), 7.45 (s, 1H), 8.05 (s, 1H), 8.4 (s, 1H) and 9.45 (s,1H). m/z 484 (M+H)⁺.

The following compounds were synthesised in an analogous fashion fromeither3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamideor3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamideand the appropriate halogenated heterocycle:

Example Structure m/z NMR 34a

512(M + H)⁺ ¹H NMR δ (CDCl₃): 1.3 (d, 3 H), 2.3 (m, 2 H),2.5 (s, 3 H),3.3 (s, 3 H), 3.45-3.55 (m, 2 H), 4.1-4.35 (m, 4 H), 4.55 (m, 1 H), 6.9(d, 1 H), 7.2 (d,1 H), 7.35 (s, 1 H), 8.05 (s, 1 H), 8.1 (s, 1 H),8.2(d, 1 H), 8.3 (s, 1 H) and 9.45 (s, 1 H). 34b***

479(M + H)⁺ ¹H NMR δ (CDCl₃): 1.3 (d, 3 H), 2.3 (m, 2 H),2.5 (s, 3 H),3.3 (s, 3 H), 3.45-3.55 (m, 2 H), 4.2(t, 2 H), 4.55 (m, 1 H), 4.65 (t, 2H), 6.9 (d,1 H), 7.25 (d, 1 H), 7.35 (d, 1 H), 8.05 (s, 1 H), 8.3(s, 1H), 8.45 (s, 1 H) 8.8 (s, 1 H) and 9.45 (s, 1 H). 34c

478(M + H)⁺ ¹H NMR δ (CDCl₃): 1.3 (d, 3 H), 2.3 (m, 2 H),2.5 (s, 3 H),3.3 (s, 3 H), 3.45-3.55 (m, 2 H),4.15-4.35 (m, 4 H), 4.55 (m, 1 H), 6.8(d, 1 H),6.95 (d, 1 H), 7.2 (s, 1 H), 7.35 (s, 1 H), 8.0 (dd,1 H), 8.05(s, 1 H), 8.35 (d, 1 H), 8.5 (s, 1 H) and9.5 (s, 1 H). 34d

484(M + H)⁺ ¹H NMR δ (CDCl₃): 1.3 (d, 3 H), 2.2 (m, 2 H),2.5 (s, 3 H),3.3 (s, 3 H), 3.45-3.55 (m, 2 H),4.15 (t, 2 H), 4.4 (t, 2 H), 4.55 (m, 1H), 7.0 (d,1 H), 7.3 (d, 1 H), 7.45 (s, 1 H), 7.65 (s, 1 H), 8.05(s, 1H), 8.4 (s, 1 H) and 9.45 (s, 1 H). 34e

498(M + H)⁺ ¹H NMR δ (CDCl₃): 1.3 (d, 3 H), 2.25 (m, 2 H),2.45 (s, 3 H),2.5 (s, 3 H), 3.3 (s, 3 H), 3.45-3.55(m, 2 H), 4.1-4.2 (t, 4 H), 4.55(m, 1 H), 7.0 (d,1 H), 7.35 (d, 2 H), 8.05 (s, 1 H), 8.4 (s, 1 H)and9.45 (s, 1 H). 34f**

486(M + H)⁺ ¹H NMR δ (CDCl₃): 1.3 (d, 3 H), 2.25 (m, 2 H),2.5 (s, 3 H),3.3 (s, 3 H), 3.4-3.55 (m, 2 H), 3.7 (s,3 H), 4.1-4.2 (t, 4 H), 4.5 (m,1 H), 6.7 (s, 1 H),6.95 (s, 1 H), 7.2 (d, 1 H), 7.3 (d, 2 H) and 8.6(s,1 H). **The compound was partially crystallised from diethyl ether;mpt; melting onset 80.7° C. ***Example 34b,3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide,was also prepared in the following manner.

A mixture of3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide(25.4 g, 80.0 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (17.4 g,88.0 mmol) and potassium carbonate (33.1 g, 240 mmol) in acetonitrile(254 mL) was heated at 60° C. for 24 hours. The solvent was removed byevaporation and the residue partitioned between ethyl acetate (15 vol)and water (10 vol). The layers were separated, the aqueous layer furtherextracted into ethyl acetate (2×10 vol) and the combined organics washedwith water (2×5 vol), brine (5 vol), dried (MgSO₄), filtered,concentrated in vacuo. The residue was chromatographed on silica,eluting with ethyl acetate, to give the desired compound as a foam (33.7g). The pure material was dissolved in hot tert-butylmethyl ether (30vols), seeded with genuine crystalline sample (the seeds were isolatedfrom a small scale crystallisation where material was dissolved in aminimum amount of hot tert-butylmethyl ether then isohexane added andthe flask scratched to promote crystallisation) and stirred overnight.The mixture was cooled and the crystalline material (melting onset110.3° C.) collected by filtration (29.1 g).

¹H NMR 8 (d₆-DMSO): 1.27 (d, 3H), 2.30 (quin, 2H), 2.49 (s, 3H), 3.31(s, 3H), 3.47-3.56 (m, 2H), 4.10 (t, 2H), 4.57 (t, 2H), 4.79 (td, 1H),7.13 (t, 1H), 7.48 (td, 1H), 7.57 (td, 1H), 8.36 (d, 1H), 8.56 (d, 1H),8.69 (d, 1H), 9.26 (d, 1H), 11.00 (s, 1H); m/z 479 (M+H)⁺

This crystalline form could be converted to a different crystalline formby placing approximately 30 mg of material in a vial with a magneticflea, and adding approximately 1 mL of water. A few (3) drops ofmethanol were added to this, and the vial was sealed with a lid. Theslurry was then left to stir on a magnetic plate at RT (25° C.). After 3days, the sample was removed from the plate, the lid removed and theslurry left to dry under ambient conditions. The new crystalline form(melting onset 110.2° C.) was shown to be different by XRPD analysis.

The title compound may also be crystallised by stirring a slurry of thecompound in water. The preparation of3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamideis described below:

3-Hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

10% Palladium on charcoal (700 mg) was added to a solution of3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide(7.0 g, 17.2 mmol) in ethanol (125 mL) and the mixture stirred at RTunder a hydrogen atmosphere for 4 hours. The catalyst was removed byfiltration and the ethanol evaporated in vacuo. The residue wascrystallised from ethyl acetate to give the desired compound (4.22 g).¹H NMR δ (CDCl₃): 1.25 (d, 3H), 2.5 (s, 3H), 3.3 (s, 3H), 3.4-3.5 (m,2H), 4.5 (m, 1H), 6.3 (br, 1H), 6.55 (s, 1H), 6.9 (s, 1H), 6.95 (s, 1H),8.05 (s, 1H), 8.45 (s, 1H) and 9.5 (s, 1H). m/z 318 (M+H)⁺.

This reaction was also carried out using methanol as solvent and using 5bar pressure of hydrogen.

3-{[(1S)-1-Methyl-2-(methyloxyethyl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide

Oxalyl chloride (2.1 mL, 24.0 mmol) was added to a solution of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid(6.32 g, 20.0 mmol) in DCM (100 mL) and the mixture stirred at RT for 4hours. The mixture was evaporated in vacuo to a residue, which was takenup in DCM (25 ml-L) and added to a stirred mixture of2-amino-5-methylpyrazine (2.29 g, 21.0 mmol) and pyridine (1.94 mL, 24.0mmol) in DCM (100 mL) at 5° C.-10° C. The mixture was stirred at RT for18 hours, the DCM evaporated in vacuo. The residue was partitionedbetween water (50 mL) and ethyl acetate (150 mL), the organic layerwashed with brine, dried (MgSO₄) and evaporated to a residue, which waschromatographed on silica, eluting with 50% ethyl acetate in isohexane,to give the desired compound (7.0 g). ¹H NMR δ (CDCl₃): 1.3 (d, 3H), 2.5(s, 3H), 3.3 (s, 3H), 3.4-3.5 (m, 2H), 4.5 (m, 1H), 5.0 (s, 2H), 6.7 (s,1H), 7.0 (s, 1H), 7.05 (s, 1H), 7.35 (m, 5H), 8.05 (s, 1H), 8.3 (s, 1H)and 9.5 (s, 1H). m/z 408 (M+H)⁺.

The preparation of 2-amino-5 methylpyrazine is described in theliterature [Tetrahedron Lett. 2002, 9287].

The preparation of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acidwas described earlier.

The preparation of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamidewas described earlier.

The preparations of the halogenated heterocycles5-(azetidin-1-ylcarbonyl)-2-chloro-1,3-thiazole,5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine,2-(azetidin-1-ylcarbonyl)-5-chloropyrazine,5-(azetidin-1-ylcarbonyl)-2-chloropyridine and4-(azetidin-1-ylcarbonyl)-2-bromo-1,3-thiazole were described earlier.

The preparation of5-(azetidin-1-ylcarbonyl)-2-bromo-4-methyl-1,3-thiazole, used inExamples 34e-f, is described below:

5-(Azetidin-1-ylcarbonyl)-2-bromo-4-methyl-1,3-thiazole

Oxalyl chloride (0.47 mL; 5.41 mmol) was added to a solution of2-bromo-4-methyl-1,3-thiazole-5-carboxylic acid (1.0 g; 4.5 mmol) in DCM(25 mL). The mixture was stirred at RT for 18 hours, the DCM wasevaporated in vacuo, the residue azeotroped with toluene (2×5 mL) andadded to a solution of azetidine hydrochloride (503 mg; 5.41 mmol) andtriethylamine (2.3 mL; 16.2 mmol) in DCM (50 mL). The mixture wasstirred at RT for 18 hours, the DCM evaporated in vacuo, and the residuepartitioned between water (75 mL) and ethyl acetate (150 mL). Theorganic layer was washed with brine, dried (MgSO₄) and evaporated to aresidue which was chromatographed on silica, eluting with 40% ethylacetate in isohexane, to give a solid which was crystallised from ethylacetate/isohexane to give the desired compound (490 mg). ¹H NMR δ(CDCl₃): 2.35 (m, 2H), 2.55 (s, 3H) and 4.1 (t, 4H).

EXAMPLE 353-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide

Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (144mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (173mg, 0.75 mmol) in acetonitrile (5 mL) and the stirred mixture heated at120° C. in a microwave reactor for 1 hour. The mixture was cooled to RTand ambient pressure, the acetonitrile evaporated in vacuo, the residuepartitioned between water (25 mL) and ethyl acetate (50 mL). The organiclayer was washed with brine, dried (MgSO₄) and evaporated to a residuewhich was chromatographed on silica, eluting with 75% ethyl acetate inisohexane, to give the desired compound (167 mg). ¹H NMR δ (CDCl₃): 1.3(d, 6H), 2.3 (m, 2H), 2.5 (s, 3H), 4.1-4.3 (m, 4H), 4.55 (m, 1H), 6.85(d, 1H), 7.2 (d, 1H), 7.3 (s, 1H), 8.05 (s, 1H), 8.1 (s, 1H), 8.2 (s,1H) 8.3 (s, 1H) and 9.45 (s, 1H). m/z 482 (M+H)⁺.

The following compounds were prepared in an analogues fashion from3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide andthe appropriate halogenated heterocycle:

Example Structure m/z NMR 35a

449(M + H)⁺. ¹H NMR δ (CDCl₃): 1.3 (d, 6 H), 2.3 (m, 2 H),2.5 (s, 3 H),4.2 (t, 4 H), 4.55 (m, 1 H), 4.6 (t, 2 H),6.8 (d, 1 H), 7.2 (s, 1 H),7.35 (s, 1 H), 8.05 (s,1 H), 8.25 (s, 1 H), 8.35 (s, 1 H), 8.8 (s, 1 H)and9.45 (s, 1 H). 35b

448(M + H)⁺. ¹H NMR δ (CDCl₃): 1.3 (d, 6 H), 2.3 (m, 2 H),2.5 (s, 3 H),4.15 (t, 2 H), 4.3 (t, 2 H), 4.55 (m,1 H), 6.8 (d, 1 H), 6.95 (d, 1 H),7.2 (d, 1 H), 7.25(d, 1 H), 8.0 (dd, 1 H), 8.1 (s, 1 H), 8.35 (s, 1H)8.4 (s, 1 H) and 9.45 (s, 1 H). 35c*

468(M + H)⁺. ¹H NMR δ (DMSO ₆): 1.3 (d, 6 H), 2.25 (m,2 H), 2.45 (s, 3H), 3.3 (s, 3 H), 4.0-4.2 (br, 4 H),4.8 (m, 1 H), 7.2 (d, 1 H), 7.6 (d,2 H), 8.35 (s,1 H), 9.25 (s, 1 H) and 11.0 (s, 1 H). *Compound wascrystallised from ethyl acetate and isohexane; mpt; melting onset 140.4°C.

The preparation of3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide isdescribed below:

3-Hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide

10% Palladium on charcoal (550 mg) was added to a solution of3-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide(5.5 g, 14.6 mmol) in ethanol (75 mL) and THF (50 mL) and the mixturestirred at RT under a hydrogen atmosphere for 24 hours. The catalyst wasremoved by filtration and the filtrates evaporated in vacuo to a residuewhich was crystallised from ethyl acetate to give the desired compound(3.42 g).

¹H NMR δ (CDCl₃): 1.3 (d, 6H), 2.5 (s, 3H), 4.5 (m, 1H), 5.8 (br, 1H),6.5 (d, 1H), 6.9 (d, 1H), 6.95 (d, 1H), 8.05 (s, 1H), 8.4 (s, 1H) and9.5 (s, 1H). m/z 288 (M+H)⁺.

Oxalyl chloride (2.1 mL, 24.0 mmol) was added to a solution of3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (5.72 g, 20.0mmol) in DCM (100 mL) and the mixture stirred at ambient RT for 4 hours.The mixture was evaporated in vacuo to a residue, which was taken up inDCM (25 mL) and added to a stirred mixture of 2-amino-5-methylpyrazine(2.29 g, 21.0 mmol) and pyridine (1.94 mL, 24.0 mmol) in DCM (100 mL) at5° C.-10° C. The mixture was stirred at RT for 18 hours, the DCMevaporated in vacuo to a residue, which was partitioned between water(50 μL) and ethyl acetate (150 mL). The organic layer was washed withbrine, dried (MgSO₄) and evaporated to a residue which waschromatographed on silica, eluting with 30% ethyl acetate in isohexane,and crystallised from ethyl acetate/isohexane to give the desiredcompound (5.52 g).

¹H NMR δ (CDCl₃): 1.3 (d, 6H), 2.5 (s, 3H), 4.5 (m, 1H), 5.0 (s, 2H),6.6 (s, 1H), 6.95 (s, 1H), 7.0 (s, 1H), 7.35 (m, 5H), 8.05 (s, 1H), 8.3(s, 1H) and 9.5 (s, 1H). m/z 378 (M+H)⁺.

The preparations of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoicacid and 2-amino-5-methylpyrazine were described earlier.

The preparations of the halogenated heterocycles5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine,2-(azetidin-1-ylcarbonyl)-5-chloropyrazine,5-(azetidin-1-ylcarbonyl)-2-chloropyridine and5-(azetidin-1-ylcarbonyl)-2-bromo-4-methyl-1,3-thiazole were describedearlier.

EXAMPLE 363-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide(159 mg, 0.5 mmol) and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (181mg, 0.75 mmol) and bromotris(triphenylphosphine)copper (93 mg, 0.1 mmol)in DMA (5 mL) and the stirred mixture heated at 160° C. in a microwavereactor for 4 hours. The mixture was cooled to RT and ambient pressure,partitioned between water (75 mL) and ethyl acetate (50 mL), the organiclayer washed with brine, dried (MgSO₄) and evaporated in vacuo. Theresidue was chromatographed on silica, eluting with ethyl acetate, togive the desired compound that was crystallised from ether (45 mg,melting onset 113.8° C.). The compound may also be crystallised fromethyl acetate, giving rise to an alternative crystalline form (meltingonset 132.7° C.). ¹H NMR δ (CDCl₃): 1.3 (d, 3H), 2.3 (m, 2H), 2.5 (s,3H), 3.3 (s, 3H), 3.45-3.55 (m, 2H), 4.2 (t, 2H), 4.55 (m, 1H), 4.65 (t,2H), 6.75 (d, 1H), 7.05 (d, 1H), 7.25 (s, 1H), 7.3 (d, 1H), 8.0 (s, 1H),8.05 (d, 1H), 8.25 (d, 1H), 8.3 (s, 1H) and 9.45 (s, 1H). m/z 478(M+H)⁺.

The preparations of 2-(azetidin-1-ylcarbonyl)-5-bromopyridine and3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamidewere described earlier.

EXAMPLE 373-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide

Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (144mg, 0.5 mmol) and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (181 mg,0.75 mmol) and bromotris(triphenylphosphine)copper (93 mg, 0.1 mmol) inDMA (5 mL) and the stirred mixture heated at 160° C. in a microwavereactor for 4 hours. The mixture was cooled to RT and ambient pressure,partitioned between water (75 mL) and ethyl acetate (50 mL), the organiclayer washed with brine, dried (MgSO₄) and evaporated in vacuo. Theresidue was chromatographed on silica, eluting with 75% ethyl acetate inisohexane, to give the desired compound (crystallised from ether) (72mg). ¹H NMR δ (CDCl₃): 1.3 (d, 6H), 2.3 (m, 2H), 2.5 (s, 3H), 4.2 (t,2H), 4.5 (m, 1H), 4.65 (t, 2H), 6.7 (s, 1H), 7.05 (s, 1H), 7.2 (s, 1H),7.3 (d, 1H), 8.0 (br, 2H), 8.3 (br, 2H) and 9.45 (s, 1H). m/z 448(M+H)⁺. Mpt (melting onset) 125.7° C.

The preparations of 2-(azetidin-1-ylcarbonyl)-5-bromopyridine and3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide weredescribed earlier.

EXAMPLE 383-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide

A mixture of 1,1-dimethylethyl3-{[(3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylate(196 mg, 0.5 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (128mg, 0.55 mmol) and potassium carbonate (138 mg, 1.0 mmol) inacetonitrile (5 mL) was stirred in a microwave reactor at 120° C. for 4hours. The solvent was removed in vacuo and the residue partitionedbetween ethyl acetate and water. The organic layer was washed with brine(50 mL), dried (MgSO₄), filtered and the solvent removed in vacuo togive a brown oil which was chromatographed on silica, eluting with agradient of 50-100% ethyl acetate in isohexane, to give the desiredcompound as a white foam (142 mg).

¹H NMR δ (CDCl₃): 1.26 (d, 3H), 2.31 (quin, 2H), 3.33 (s, 3H), 3.43-3.53(m, 2H), 4.11-4.33 (m, 4H), 4.54 (q, 1H), 6.78 (s, 1H), 6.86 (s, 1H),7.24 (s, 1H), 7.33 (s, 1H), 7.42 (s, 1H), 8.06 (d, 1H), 8.12 (s, 1H),9.98 (s, 1H); m/z 486 (M+H)⁺

The preparations of 1,1-dimethylethyl3-{[(3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylateand 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine were describedearlier.

EXAMPLE 393-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1,3-thiazol-2-ylbenzamide

DIPEA (0.129 mL) was added to a suspension of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid (168 mg), HATU (190 mg) and 2-aminothiazole (40 mg) in DMF (2 mL)and the mixture stirred at RT for 16 hours. Water (30 mL) was added andthe mixture extracted with ethyl acetate (3×20 mL). The combined organicextracts were washed with brine, dried (MgSO₄), and evaporated to aresidue which was chromatographed on silica, eluting with 50-100% ethylacetate in isohexane, to give the desired compound (75 mg).

¹H NMR δ (CDCl₃): 1.27 (d, 3H), 2.31 (quin, 2H), 3.33 (s, 3H), 3.41-3.55(m, 2H), 4.12-4.33 (m, 4H), 4.55 (q, 1H), 6.91 (d, 1H), 6.95 (s, 1H),7.30 (s, 1H), 7.31 (d, 1H), 7.40 (s, 1H), 8.08 (s, 1H), 8.16 (s, 1H);m/z 503 (M+H)⁺

The following compounds were made in an analogous fashion from either3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(is)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid,3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]benzoicacid,3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]benzoicacid,3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid,3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(is)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid or3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]benzoicacid and the appropriate aminoheterocycle.

Example Structure m/z NMR 39a

497(M + H)⁺ ¹H NMR δ (CDCl₃): 1.28 (d, 3 H), 2.32 (quin,2 H), 3.34 (s, 3H), 3.41-3.56 (m, 2 H), 4.11-4.34 (m, 4 H), 4.55 (q, 1 H), 6.90 (s, 1H), 7.00 (t,1 H), 7.22 (s, 1 H), 7.34 (s, 1 H), 7.68 (t, 1 H), 8.08(s, 1H), 8.19 (s, 1 H), 8.23 (s, 1 H), 8.27 (d, 1 H),8.37-8.56 (m, 1 H) 39b

484(M + H)⁺ ¹H NMR δ (CDCl₃): 1.29 (d, 6 H), 1.39 (t, 3 H),2.31 (quin, 2H), 4.00 (q, 2 H), 4.11-4.34 (m,4 H), 4.54 (quin, 1 H), 6.73 (s, 1 H),6.81 (s, 1 H),7.14 (s, 1 H), 7.24 (s, 2 H), 8.09 (s, 1 H), 8.18 (s,1 H),8.39 (s, 1 H) 39c

451(M + H)⁺ ¹H NMR δ (CDCl₃): 1.29 (d, 6 H), 1.39 (t, 3 H),2.31 (quin, 2H), 3.99 (q, 2 H), 4.19 (t, 2 H), 4.53(quin, 1 H), 4.61 (t, 2 H), 6.72(s, 1 H), 6.80 (s,1 H), 7.14 (s, 1 H), 7.25 (s, 2 H), 8.25 (s, 1 H),8.36(s, 1 H), 8.79 (s, 1 H) 39d

495(M + H)⁺ ¹H NMR δ (CDCl₃): 1.27 (d, 3 H), 1.41 (d, 6 H),2.31 (quin, 2H), 3.33 (s, 3 H), 3.41-3.55 (m,2 H), 4.19 (t, 2 H), 4.30 (quin, 1 H),4.54 (q, 1 H),4.62 (t, 2 H), 6.71 (s, 1 H), 6.86 (s, 1 H), 7.18 (s,1 H),7.28 (s, 1 H), 7.30 (s, 1 H), 8.25 (s, 1 H),8.33 (s, 1 H), 8.79 (s, 1 H)39e

450(M + H)⁺ ¹H NMR δ (CDCl₃): 1.28 (d, 6 H), 1.39 (t, 3 H),2.28 (quin, 2H), 4.00 (q, 2 H), 4.18 (t, 2 H), 4.52(quin, 1 H), 4.64 (t, 2 H), 6.65(s, 1 H), 6.71 (s,1 H), 7.00 (s, 1 H), 7.16 (s, 1 H), 7.25 (s, 1 H),7.30(d, 1 H), 8.04 (d, 1 H), 8.25 (s, 1 H), 8.32 (s,1 H) 39f

463(M + H)⁺ ¹H NMR δ (CDCl₃): 1.27 (d, 3 H), 2.28 (quin,2 H), 3.34 (s, 3H), 3.43-3.54 (m, 2 H), 4.18 (t,2 H), 4.56 (q, 1 H), 4.64 (t, 2 H), 6.76(s, 1 H),7.03 (q, 1 H), 7.10 (s, 1 H), 7.27 (s, 1 H), 7.31 (d,1 H), 7.71(t, 1 H), 8.05 (d, 1 H), 8.23 (s, 1 H),8.26 (s, 1 H), 8.29 (d, 1 H),8.59 (s, 1 H) 39g

453(M + H)⁺ ¹H NMR δ (CDCl₃): 1.25 (d, 3 H), 2.27 (quin,2 H), 3.32 (s, 3H), 3.41-3.53 (m, 2 H), 4.17 (t,2 H), 4.54 (q, 1 H), 4.63 (t, 2 H), 6.78(s, 1 H),7.11 (s, 1 H), 7.15 (s, 1 H), 7.27 (s, 1 H), 7.29 9d,1 H), 8.03(d, 1 H), 8.18 (s, 1 H), 8.25 (s, 1 H),9.43 (s, 1 H) 39h

488(M + H)⁺ ¹H NMR δ (d₆-DMSO): 1.22 (d, 6 H), 2.16 (quin,2 H), 2.41 (s,3 H), 3.95 (t, 2 H), 4.26 (t, 2 H), 4.67(quin, 1 H), 7.05 (s, 1 H), 7.43(s, 1 H), 7.52 (s,1 H), 8.15 (s, 1 H), 8.25 (s, 1 H), 13.32 (s, 1 H)39i*

422(M + H)⁺ ¹H NMR δ (CDCl₃): 1.28 (d, 6 H), 2.27 (quin,2 H), 4.16 (t, 2H), 4.51 (quin, 1 H), 4.62 (t, 2 H),6.68 (s, 1 H), 6.72 (s, 1 H), 7.08(s, 1 H), 7.23 (s,1 H), 7.28 (d, 1 H), 7.46 (s, 1 H), 7.99 (d, 1 H),8.24(s, 1 H), 9.25 (s, 1 H) 39j*⁺

452(M + H)⁺ ¹H NMR δ (CDCl₃): 1.25 (d, 3 H), 2.28 (quin,2 H), 3.33 (s, 3H), 3.42-3.55 (m, 2 H), 4.16 (t,2 H), 4.54 (q, 1 H), 4.62 (t, 2 H), 6.73(s, 1 H),6.75 (s, 1 H), 7.12 (s, 1 H), 7.28 (d, 1 H), 7.32 (s,1 H), 7.43(s, 1 H), 8.00 (d, 1 H), 8.24 (s, 1 H),9.78 (s, 1 H) 39k*⁺⁺

423(M + H)⁺ ¹H NMR δ (CDCl₃): 1.28 (d, 6 H), 2.31 (quin,2 H), 4.19 (t, 2H), 4.52 (quin, 1 H), 4.61 (t, 2 H),6.76-6.78 (m, 2 H), 7.19 (s, 1 H),7.27 (s, 1 H),7.37 (s, 1 H), 8.29 (s, 1 H), 8.74 (s, 1 H), 10.03 (s,1 H)39l*

453(M + H)⁺ ¹H NMR δ (CDCl₃): 1.25 (d, 3 H), 2.31 (quin,2 H), 3.33 (s, 3H), 3.42-3.54 (m, 2 H), 4.18 (t,2 H), 4.53 (q, 1 H), 4.61 (t, 2 H), 6.78(s, 1 H),6.83 (s, 1 H), 7.22 (s, 1 H), 7.35 (s, 2 H), 8.31 (s,1 H), 8.73(s, 1 H), 10.38 (s, 1 H) 39m*

456(M + H)⁺ ¹H NMR δ (CDCl₃): 1.28 (d, 6 H), 2.31 (quin,2 H), 4.15 (t, 2H), 4.25 (t, 2 H), 4.53 (quin, 1 H),6.79 (s, 2 H), 7.20 (s, 1 H), 7.26(s, 1 H), 7.33 (s,1 H), 8.08 (s, 1 H), 8.10 (s, 1 H), 10.44 (s, 1 H)*The reactions were carried out using 1,1-dimethylethyl3-amino-1H-pyrazole-1-carboxylate as the amino heterocycle, theresultant products were dissolved in acetonitrile (4 mL) and ethanol(0.5 mL) and heated in a microwave reactor at 150° C. for 12 minutes.The mixtures were allowed to cool then concentrated in vacuo to give thedesired products. ⁺This compound was crystallised from ethyl acetate andisohexane using vapour diffusion techniques. ⁺⁺This compound wascrystallised from acetonitrile, melting point (melting onset) 108.5° C.

The preparation of 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylatewas described earlier. The preparation of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid is given below:

3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid

A mixture of methyl3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (240 mg, 0.1mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (278 mg, 1.2 mmol)and potassium carbonate (276 mg, 2.0 mmol) in DMA (5 mL) was stirred at120° C. for 16 hours. The solution was poured into water (30 mL) andacidified with 1N hydrochloric acid before being extracted with ethylacetate (3×20 mL). The combined organics were washed with brine (20 mL),dried (MgSO₄), filtered and the solvent removed in vacuo to give methyl3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate(as evidenced by LCMS data only m/z 435 (M+H)⁺) as a brownish oil (550mg). The crude methyl3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate(434 mg, 1 mmol) was dissolved in THF (15 mL) and methanol (5 mL) then1N aqueous Lithium hydroxide solution (2 mL) added followed by thedropwise addition of water until a clear solution obtained. The mixturewas stirred was stirred for 4 hours at RT and the organics removed byevaporation. The aqueous solution was filtered, extracted with ethylacetate (10 mL) and the aqueous layer acidified with 2N hydrochloricacid. The acidified layer was extracted with ethyl acetate (3×30 mL) andthe combined organic extracts washed with water (10 mL), brine (10 mL)and concentrated in vacuo to give the desired compound as a pale oil(375 mg). ¹H NMR δ (CDCl₃): 1.27 (d, 3H), 2.32 (quin, 2H), 3.34 (s, 3H),3.42-3.55 (m, 2H), 4.13-4.34 (m, 4H), 4.54 (q, 1H), 6.93 (s, 1H), 7.40(s, 1H), 7.48 (s, 1H), 8.08 (s, 1H), 8.19 (s, 1H), m/z 421 (M+H)⁺

3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]benzoicacid,3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]benzoicacid and3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid were made in an analogous fashion from either methyl3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate or methyl3-hydroxy-5-[(1-methylethyl)oxy]benzoate and the appropriate halogenatedheterocycle.

Structure m/z NMR

391(M + H)⁺ ¹H NMR δ (CDCl₃): 1.29 (d, 6 H), 2.31 (quin,2 H), 4.11-4.35(m, 4 H), 4.53 (quin, 1 H), 6.87(s, 1 H), 7.37 (s, 1 H), 7.42 (s, 1 H),8.09 (s,1 H), 8.19 (s, 1 H)

358(M + H)⁺ ¹H NMR δ (d₆-DMSO): 1.28 (6 H, d), 2.26-2.34 (2 H, quin),4.10 (2 H, t), 4.56 (2 H, t),4.65-4.71 (1 H, quin), 7.11 (1 H, t), 7.29(1 H,s), 7.33 (1 H, s), 8.53 (1 H, s), 8.66 (1 H, s)

388(M + H)⁺ ¹H NMR δ (CDCl₃): 1.27 (d, 3 H), 2.31 (quin,2 H), 3.33 (s, 3H), 3.41-3.55 (m, 2 H), 4.20 (t,2 H), 4.50-4.57 (m, 1 H), 4.62 (t, 2 H),6.92 (t,1 H), 7.39 (s, 1 H), 7.49 (s, 1 H), 8.25 (s, 1 H),8.78 (s, 1 H)

The preparation of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]benzoicacid is described below:

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]benzoicacid

A mixture of methyl 3-hydroxy-5-[(1-methylethyl)oxy]benzoate (0.84 g, 4mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (1.16 g, 4.8 mmol),cesium carbonate (3.92 g, 1.2 mmol) andbromotris(triphenylphosphine)copper(I) (744 mg, 0.8 mmol) in DMA (20 mL)was stirred in a microwave reactor at 160° C. for 6 hours. The mixturewas diluted with water (100 mL), washed with ethyl acetate (2×20 mL) andthe aqueous layer filtered then acidified with 2N hydrochloric acid. Theacidic layer was extracted with ethyl acetate (3×50 mL), the combinedorganics washed with water (2×20 mL), brine (20 mL), dried (MgSO₄), andthe solvent removed in vacuo. The residue was triturated with ether togive the desired compound as a white solid (1.06 g). ¹H NMR 8 (d₆-DMSO):1.28 (d, 6H), 2.28 (quin, 2H), 4.08 (t, 2H), 4.59 (t, 2H), 4.69 (quin,1H), 6.98 (t, 1H), 7.10 (s, 1H), 7.28 (s, 1H), 7.56 (d, 1H), 7.99 (d,1H), 8.41 (s, 1H); m/z 357 (M+H)⁺

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid was prepared in an analogous fashion from2-(azetidin-1-ylcarbonyl)-5-bromopyridine and methyl3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate.

Structure m/z NMR

387(M + H)⁺ ¹H NMR δ (CDCl₃): 1.25 (d, 3 H), 2.28 (quin,2 H), 3.33 (s, 3H), 3.40-3.54 (m, 2 H), 4.20 (t,2 H), 4.53 (quin, 1 H), 4.64 (t, 2 H),6.79 (t,1 H), 7.25 (s, 1 H), 7.42 (s, 1 H), 7.99-8.11 (m,1 H), 8.19-8.35(m, 1 H)

The preparations of methyl3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate, methyl3-hydroxy-5-[(1-methylethyl)oxy]benzoate and the appropriate halogenatedheterocycles were described earlier.

3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3-ylbenzamide,Example 39k, was also prepared in the following manner from1,1-dimethylethyl3-[({3-hydroxy-5-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate.

1,1-Dimethylethyl3-[({3-hydroxy-5-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate(56.3 g, 0.16 mol) was dissolved in acetonitrile (500 mL) and charged toa 3 L fixed vessel. Potassium carbonate—325 mesh—(64.5 g, 0.47 mol) wasadded, followed by 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (33.5 g,0.17 mol) with a 100 mL acetonitrile charge wash. The mixture wasstirred rapidly and warmed to 60° C. under nitrogen. Additionalacetonitrile (250 mL) was added followed, after 1.5 hours, by theaddition of DMF (150 mL) to dissolve residual solid material. Thereaction was stirred overnight then allowed to cool to RT and filtered.The filtrate was concentrated under vacuum to remove the acetonitrileand the residual solution poured into water (1500 mL) with stirring. Theprecipitated solid was filtered, dissolved in DCM (560 mL), washed with1:1 brine/saturated aqueous solution of sodium hydrogen carbonate (2×500mL) and dried (MgSO₄). The organic solution was filtered and TFA (50mL). The solution was stirred at RT for 3 hours. Additional TFA (50 mL)was added and the mixture stirred at 30° C. for a further 3 hours thenat RT overnight. The solvent was removed under vacuum and the residueazeotroped with toluene. The orange oily residue was dissolved in ethylacetate (500 mL) and washed with a saturated solution of sodium hydrogencarbonate (2×500 mL), brine (500 mL), dried (MgSO₄) and concentrated toleave a pale yellow waxy solid (64 g). The solid was triturated withethyl acetate (200 mL) at 45° C. for 2 hours, filtered, washed withethyl acetate and dried in a vacuum oven at 40° C. overnight to leave awhite solid (52 g). The crude solid was columned on silica, eluting witha mixture of a 7N ammonia in methanol solution in DCM (0.5-6.5% methanolgradient), to give pure desired material [pure 1] (23.6 g, 99.1% pure byHPLC) and less pure material recovered from mixed fractions and previousliquors (34.5 g, 82.8% pure by HPLC). The impure material was dissolvedin DCM (50 mL) and a white solid crystallised out. The solid was removedby filtration and washed with DCM to give pure desired material [pure 2](6.5 g, 98.3% pure by HPLC). The filtrate was columned on silica,eluting with 7N ammonia in methanol solution in DCM (0-5% methanolgradient), to give the desired material [pure 3] (18.3 g, 98.7% pure byHPLC). Pures 1, 2 & 3 were combined (48.4 g) and charged to a 3 L fixedvessel. Ethyl acetate (500 mL, 10 vol) was added and the mixture washeated to reflux with stirring, additional ethyl acetate (400 mL, 8 vol)was added and the remaining solid material removed by hot filtration.The filtrate was cooled to 60° C. and isohexane (250 mL) added dropwise.The slurry was cooled to 20° C. over approx 1 hour and then stirred atRT overnight. The slurry was filtered and the solid washed withisohexane (2×200 mL) then dried in a vacuum oven at 40° C. to leave awhite solid (34.5 g). This solid was further dried in a vacuum oven at60° C. overnight to leave the desired compound as a white powder (33.1g). This is a different crystal form to that previously described,melting point (melting onset) 113.8° C.

The preparation of 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine wasdescribed earlier.

The preparation of 1,1-dimethylethyl3-[({3-hydroxy-5-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylateis described below.

1,1-Dimethylethyl3-[({3-hydroxy-5-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate

1,1-Dimethylethyl3-[({3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate(76.4 g, 0.17 mol) was dissolved in ethanol (750 mL, 10 vol) and 10%palladium on charcoal (water wet) (7.5 g) added. The mixture washydrogenated for 18 hours at 25° C. and a pressure of 5 bar. Thecatalyst was removed by filtration through Celite® and the cake washedwith methanol (250 mL). The combined filtrate was concentrated undervacuum to leave a beige foamy solid which was chromatographed on silica,eluting with 10-70% ethyl acetate in isohexane, to give the desiredmaterial as a white foam solid (56.4 g). ¹H NMR δ (CDCl₃): 1.30 (d, 6H),1.64 (s, 9H), 4.49-4.55 (m, 1H), 6.67 (t, 1H), 6.98 (d, 2H), 7.10 (d,1H), 8.02 (d, 1H), 9.21 (s, 1H); m/z 360 (M−H)⁻

1,1-Dimethylethyl3-[({3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate

A solution of oxalyl chloride (76 mL, 0.87 mol) in DCM (125 mL) wasadded dropwise to a slurry of3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (50 g, 0.17mol) and DMF (1 mL) in DCM (300 mL). The reaction was stirred at RT for2 hours then the solvent removed under vacuum and the residue azeotropedwith toluene (200 mL). The oily residue was dissolved in dry pyridine(100 mL) and the mixture added, over 5 minutes, to a solution of1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (38.4 g, 0.21 mol)in dry pyridine (325 mL) under nitrogen. The reaction was stirred at RTfor 1 hour, the solvent removed under vacuum and the residue azeotropedwith toluene. The residue was partitioned between DCM (500 mL) and water(500 mL) and the organic layer washed with a saturated aqueous solutionof sodium hydrogen carbonate (500 mL), brine (500 mL) and dried (MgSO₄).The organic solution was concentrated under vacuum and the residue twiceazeotroped with toluene to leave an orange resin (88.8 g). The resin waschromatographed on silica, eluting with 25-50% ethyl acetate inisohexane, to give the desired material as a pale yellow foam (76.4 g).¹H NMR δ (CDCl₃): 1.33 (d, 6H), 1.56 (s, 9H), 4.49-4.55 (m, 1H), 5.04(s, 2H), 6.69 (t, 1H), 7.00 (t, 1H), 7.06-7.07 (m, 1H), 7.17 (d, 1H),7.32-7.45 (m, 5H), 8.04 (d, 1H), 9.48 (s, 1H); m/z 450 (M−H)⁻

The preparations of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoicacid and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate weredescribed earlier.

EXAMPLE 403-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide

A solution ofN-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide(0.62 mmol) in acetonitrile (5 mL), was treated with potassium carbonate(1.24 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (0.68mmol), before being heated to 120° C. in a microwave reactor for 4.5hours. The mixture was evaporated in vacuo, before being partitionedbetween DCM (20 mL) and water (20 mL). The organics were evaporated invacuo then chromatographed on silica, eluting with 0-10% methanol inethyl acetate, to give the desired compound as a white foam (160 mg).

¹H NMR δ (d₆-DMSO): 1.25 (d, 3H), 2.24 (s, 3H), 2.26 (m, 2H), 3.30 (s,3H), 3.50 (m, 2H), 3.66 (s, 3H), 4.05 (t, 2H), 4.37 (t, 2H), 4.78 (m,1H), 6.42 (s, 1H), 7.03 (t, 1H), 7.38 (t, 1H), 7.51 (t, 1H), 8.23 (d,1H), 8.34 (d, 1H), 10.76 (s, 1H); m/z 514, 516 (M+H)⁺

The preparation of 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine wasdescribed earlier. The preparation ofN-(1,5-dimethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamideis described below:

N-(1,5-Dimethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide

A solution ofN-(1,5-dimethyl-1H-pyrazol-3-yl)-3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide(2.57 mmol) in ethanol (40 mL), under argon was treated with 10%palladium on carbon (100 mg, wetted with 0.1 mL water and 1 mL ethanol).The flask was evacuated and filled with hydrogen, this procedure wasrepeated 4 times. The mixture was left to stir at RT overnight under anatmosphere of hydrogen then the reaction filtered through Celite® andthe cake washed with ethanol (50 mL) and ethyl acetate (50 mL). Thecombined organic layers were evaporated in vacuo to give the desiredcompound as a white foam (597 mg). ¹H NMR δ (d₆-DMSO): 1.23 (d, 3H),2.25 (s, 3H), 3.31 (s, 3H), 3.47 (m, 2H), 3.66 (s, 3H), 4.66 (m, 1H),6.40 (s, 1H), 6.46 (t, 1H), 6.95 (t, 1H), 7.06 (t, 1H), 9.60 (s, 1H),10.49 (s, 1H); m/z 320 (M+H)⁺

N-(1,5-Dimethyl-1H-pyrazol-3-yl)-3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide

A solution of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid(4.11 mmol) in DMF (10 mL) was treated with the1,5-dimethyl-1H-pyrazol-3-ylamine (4.52 mmol), DIPEA (5.93 mmol) andHATU (3.85 mmol) and stirred at RT overnight, under an argon atmosphere.The mixture was poured onto water (100 mL) and extracted with ethylacetate (3×100 mL). The organic layer was washed with brine (20 mL) andevaporated in vacuo before chromatography on silica, eluting with 20-80%ethyl acetate in isohexane, to afford the desired compound as a yellowoil (1.05 g).

¹H NMR δ (d₆-DMSO): 1.23 (d, 3H), 2.25 (s, 3H), 3.30 (s, 3H), 3.48 (m,2H), 3.67 (s, 3H), 4.71 (m, 1H), 5.16 (s, 2H), 6.42 (s, 1H), 6.73 (t,1H), 7.20 (t, 1H), 7.26 (t, 1H), 7.34 (m, 1H), 7.41 (m, 2H), 7.46 (m,2H), 10.62 (s, 1H); m/z 410 (M+H)⁺

The preparation of3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acidwas described earlier.

The 1,5-dimethyl-1H-pyrazol-3-ylamine was prepared according to theliterature route [J. Het. Chem., (1982), 19, 1267].

EXAMPLE 413-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzamide

A solution ofN-(1,5-dimethyl-1H-pyrazol-3-yl)-3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxybenzamide(0.61 mmol) in acetonitrile (5 mL), was treated with the potassiumcarbonate (1.23 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine(0.68 mmol), before being heated to 120° C. in a microwave reactor for 4hours. The mixture was filtered and evaporated in vacuo before beingchromatographed on silica, eluting with 0-5% methanol in ethyl acetate,to give the desired compound as a white foam (175 mg).

¹H NMR δ (d₆-DMSO): 2.27 (m, 5H), 3.66 (s, 3H), 4.06 (t, 2H), 4.37 (t,2H), 4.65 (m, 1H), 4.73 (m, 1H), 4.77 (m, 1H), 4.85 (m, 1H), 5.10 (m,1H), 6.42 (s, 1H), 7.16 (t, 1H), 7.45 (t, 1H), 7.60 (t, 1H), 8.23 (d,1H), 8.35 (d, 1H), 10.71 (s, 1H) m/z 520 (M+H)⁺

The preparation of 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine wasdescribed earlier. The preparation ofN-(1,5-dimethyl-1H-pyrazol-3-yl)-3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxybenzamideis described below:

N-(1,5-Dimethyl-1H-pyrazol-3-yl)-3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxybenzamide

A solution ofN-(1,5-dimethyl-1H-pyrazol-3-yl)-3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide(1.89 mmol) in ethanol (30 mL) was treated with 10% palladium on carbon(78 mg, wetted with 1 mL ethanol). The flask was evacuated and filledwith hydrogen and this procedure repeated a further 4 times. The mixturewas left to stir at RT overnight under an atmosphere of hydrogen thenthe mixture filtered through Celite® and the cake washed with ethanol(50 mL) and ethyl acetate (50 mL). The combined organics were evaporatedin vacuo to give the desired compound as a white foam (613 mg).

¹H NMR δ (d₆-DMSO): 2.52 (s, 3H), 3.66 (s, 3H), 4.66 (m, 2H), 4.77 (m,2H), 4.97 (m, 1H), 6.41 (s, 1H), 6.56 (t, 1H), 7.02 (m, 1H), 7.15 (t,1H), 10.52 (s, 1H); m/z 326 (M+H)⁺

N-(1,5-Dimethyl-1H-pyrazol-3-yl)-3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide

A solution of3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoicacid (2.96 mmol) in DMF (5 mL) was treated with1,5-dimethyl-1H-pyrazol-3-ylamine (3.11 mmol), DIPEA (5.93 mmol) andHATU (3.85 mmol) and stirred at RT overnight. The mixture was pouredinto water (100 mL) and extracted with ethyl acetate (3×75 mL). Theorganics were washed with brine, dried (MgSO₄) and evaporated in vacuobefore chromatography on solica, eluting with 50-100% ethyl acetate inisohexane, to give the desired compound as a colourless glass (784 mg).¹H NMR δ (d₆-DMSO): 2.81 (s, 3H), 3.67 (s, 3H), 4.66 (m, 2H), 4.78 (m,2H), 5.04 (m, 1H), 5.69 (s, 2H), 6.43 (s, 1H), 6.85 (t, 1H), 7.28 (m,1H), 7.32 (m, 1H), 7.35 (m, 1H), 7.41 (m, 2H), 7.47 (m, 2H), 10.64 (s,1H); m/z 416 (M+H)⁺

The preparations of3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoicacid and 1,5-dimethyl-1H-pyrazol-3-ylamine were described earlier.

EXAMPLE 423-{[6-(Azetidin-1-ylcarbonyl)pyridazin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide

A mixture of 3-(azetidin-1-ylcarbonyl)-6-chloropyridazine (45 mg, 0.23mmol),3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide(70 mg, 0.23 mmol) and potassium carbonate (63 mg, 0.46 mmol) inacetonitrile (3 mL) was stirred in a Smith Creator microwave at 130° C.for 1 hour. The solid was filtered off and the solvent was removed invacuo. The residue was purified by reverse phase preparative HPLC,eluting with 5-95% acetonitrile in water (+0.2% TFA), followed bypassage through a Silicycle Si-Carbonate cartridge, eluting withmethanol, to give the desired product as a colourless solid (97 mg). ¹HNMR δ (CDCl₃): 1.34 (3H, d), 1.66 (3H, s), 2.33-2.41 (2H, m), 3.40 (3H,s), 3.48-3.52 (1H, m), 3.56-3.60 (1H, m), 3.79 (3H, s), 4.27 (2H, d),4.58-4.62 (1H, m), 4.76 (2H, t), 6.79 (1H, d), 6.97 (1H, t), 7.25-7.29(3H, m), 7.35-7.36 (1H, m), 8.26-8.28 (1H, m), 8.49 (1H, s); m/z 467(M+H)⁺. The preparation of3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamidewas described earlier.

The preparation of 3-(azetidin-1-ylcarbonyl)-6-chloropyridazine isdescribed below:

3-(Azetidin-1-ylcarbonyl)-6-chloropyridazine

Phosphorus oxychloride (50 mL) was added to6-hydroxypyridazine-3-carboxylic acid (9.82 g, 70.05 mmol) and theresulting solution heated to reflux. After 45 mins the solution wasallowed to cool and the excess of phosphorus oxychloride was removedunder reduced pressure. THF (50 mL) was added to the black residue andthe resulting solution cooled to 0° C. Triethylamine (9.77 mL, 70.05mmol) and azetidine (4.0 g, 70.05 mmol) were added dropwise. Theresulting mixture was allowed to warm to RT and stirred overnight. Thevolatiles were removed under reduced pressure and water (50 mL) added,then the residue was adjusted to pH8 using sodium hydroxide solution.The aqueous layer was extracted five times with ethyl acetate, thecombined organics dried (MgSO₄) and the solvent removed to give thecrude product as a dark oil. A sample was purified by preparative HPLC,eluting with 5-95% acetoniltrile in water (+0.2% TFA), and gave thetitle compound as a colorless solid (135 mg).

¹H NMR δ (CDCl₃): 2.39-2.47 (2H, m), 4.30 (2H, t), 4.82 (2H, t), 7.64(1H, d), 8.21 (1H, d); m/z 198 (M+H)⁺.

EXAMPLE 433-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(4-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-tetrahydrofuran-3-yloxy]benzoicacid (200 mg, 0.52 mmol), HATU (475 mg, 1.25 mmol) and2-amino-4-methylthiazole (119 mg, 1.04 mmol) were suspended in DMF (2mL). DIPEA (0.220 mL, 1.26 mmol) was then added and the reaction mixturestirred at RT for 16 hours. The DMF was removed in vacuo and water (15mL) added. The mixture was extracted with ethyl acetate (3×20 mL) andthe extracts combined, washed with water (15 mL), 1N hydrochloric acid(10 mL), water (10 mL), a saturated aqueous solution of sodiumbicarbonate (10 mL), brine (10 mL), dried (MgSO₄), filtered, andevaporated in vacuo. The residue was chromatographed on silica, elutingwith a gradient of 60-100% ethyl acetate in isohexane, to give thedesired compound (70 mg).

¹H NMR δ (CDCl₃): 2.13-2.29 (m, 2H), 2.32 (s, 3H), 2.34-2.42 (m, 2H),3.89-4.02 (m, 4H), 4.26 (t, 2H), 4.69 (t, 2H), 4.96-4.99 (m, 1H), 6.57(d, 1H), 6.94 (t, 1H), 7.29 (t, 1H), 7.33 (t, 1H), 8.35 (d, 1H), 8.85(d, 1H), 9.72 (s, 1H); m/z 482 (M+H)⁺, 480 (M−H)⁻

The following compounds were prepared in an analogous fashion from3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid and the appropriate aminoheterocycle.

Example Structure m/z NMR 43a

482(M + H)⁺ ¹H NMR δ (CDCl₃): 2.12-2.29 (m, 2 H),2.34-2.42 (m, 2 H),2.38 (s, 3 H), 3.88-4.02 (m, 4 H), 4.26 (t, 2 H), 4.68 (t, 2H),4.96-5.00 (m, 1 H), 6.93 (t, 1 H), 6.98 (s,1 H), 7.34 (t, 1 H), 7.37(t, 1 H), 8.34 (d,1 H), 8.84 (d, 1 H) 43b

479(M + H)⁺ ¹H NMR δ (CDCl₃): 1.46 (t, 3 H), 2.13-2.29 (m, 2 H),2.34-2.42 (m, 2 H), 3.88-4.02 (m, 4 H), 4.06 (q, 2 H), 4.26 (t, 2H),4.69 (t, 2 H), 4.96-5.00 (m, 1 H), 6.78 (d,1 H), 6.88 (t, 1 H), 7.24(t, 1 H), 7.30-7.31(m, 1 H), 7.32 (d, 1 H), 8.34 (d, 1 H), 8.36(s, 1 H),8.86 (d, 1 H) 43c

439(M + H)⁺491(M − H)⁻ ¹H NMR δ (CDCl₃): 1.48 (d, 6 H), 2.13-2.29 (m, 2H), 2.34-2.42 (m, 2 H), 3.88-4.02 (m, 4 H), 4.26 (t, 2 H), 4.36(septet,1 H), 4.69 (t, 2 H), 4.97-5.00 (m, 1 H), 6.77(d, 1 H), 6.88 (t,1 H), 7.24-7.25 (m, 1 H),7.31-7.31 (m, 1 H), 7.35 (d, 1 H), 8.33 (d,1H), 8.34 (s, 1 H), 8.86 (d, 1 H) 43d*

451(M + H)⁺449(M − H)⁻ ¹H NMR δ (CDCl₃): 2.13-2.29 (m, 2 H),2.34-2.42(m, 2 H), 3.88-4.02 (m, 4 H),4.26 (t, 2 H), 4.69 (t, 2 H), 4.96-5.00(m,1 H), 6.84 (s, 1 H), 6.87 (t, 1 H), 7.28 (t,1 H), 7.31 (t, 1 H), 7.46(d, 1 H), 8.36 (d,1 H), 8.83 (d, 1 H), 9.45 (s, 1 H), 10.05 (s,1 H) 43e

479(M + H)⁺477(M − H)⁻ ¹H NMR δ (CDCl₃): 2.11-2.24 (m, 2 H),2.26 (s, 3H), 2.33-2.41 (m, 2 H), 3.61 (s,3 H), 3.87-4.00 (m, 4 H), 4.25 (t, 2 H),4.68(t, 2 H), 4.93-4.97 (m, 1 H), 6.58 (s, 1 H),6.86 (t, 1 H), 7.24 (t,1 H), 7.28 (s, 1 H), 8.32(d, 1 H), 8.84 (d, 1 H), 8.85 (s, 1 H) *Thereaction was carried out using 1,1-dimethylethyl3-amino-1H-pyrazole-1-carboxylate as the amino heterocycle, theresultant product was dissolved in acetonitrile and heated in amicrowave reactor at 150° C. for 5-10 minutes. The mixtures were allowedto cool then concentrated in vacuo to give the desired products. Thepreparation of 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate wasdescribed earlier. The preparation of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid is described below:

3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid

Methyl3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate(7.02 mmol) was dissolved in THF (50 mL), 1N sodium hydroxide (7.0 mL)was added followed by water (50 mL) and the resultant solution stirredat RT for 4 hours. The organics were removed in vacuo, the aqueoussolution filtered and extracted with ethyl acetate (30 mL). The aqueouslayer was acidified with 2N hydrochloric acid, extracted with ethylacetate (3×50 mL), and the organic extracts washed with water (10 mL),brine (10 mL) then evaporated to dryness to give the desired material asa white foam (2.33 g). ¹H NMR δ (CDCl₃): 2.14-2.30 (m, 2H), 2.34-2.42(m, 2H), 3.89-3.94 (m, 2H), 3.97-4.02 (m, 2H), 4.28 (t, 2H), 4.69 (t,2H), 4.97-5.00 (m, 1H), 6.94 (t, 1H), 7.48 (t, 2H), 8.34 (d, 1H), 8.85(d, 1H); m/z 386 (M+H)⁺, 384 (M−H)⁻

Methyl3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

A solution of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate(2.5 g, 10.5 mmol), potassium carbonate (2.9 g, 21.0 mmol) and2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (2.48 g, 12.6 mmol) in DMA(25 mL) was heated at 120° C. for 2 hours. The solution was diluted withethyl acetate (150 mL), washed with water (3×50 mL), brine (20 mL),dried (MgSO₄), filtered and the solvent removed in vacuo. The residuewas purified by chromatography on silica, eluting with 0-50% ethylacetate in isohexane, to give the desired compound as a colourless oil(2.8 g). ¹H NMR δ (CDCl₃): 2.13-2.29 (m, 2H), 2.34-2.41 (m, 2H),3.88-4.04 (m, 4H), 3.90 (s, 3H), 4.25 (t, 2H), 4.68 (t, 2H), 4.96-5.00(m, 1H), 6.91 (t, 1H), 7.43 (d, 2H), 8.32 (d, 1H), 8.85 (d, 1H); m/z 386(M+H)⁺, 384 (M−H)⁻

Methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

Methyl 3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate(25.0 g, 76.2 mmol) was dissolved in THF (150 mL) and ethanol (150 mL).10% Palladium on carbon (30 mg) was added and the mixture placed under ahydrogen atmosphere and left to stir at RT until the reaction wascomplete. The catalyst was removed by filtration through diatomaceousearth and the filtrate was concentrated in vacuo to give an orange oilwhich crystallised on standing. The solid was filtered off and washedwith diethyl ether to give the desired product as a white solid (13.75g).

¹H NMR δ (CDCl₃): 2.1-2.3 (2H, m), 3.9 (3H, s), 3.9-3.95 (2H, m),3.97-4.05 (2H, m), 4.95 (1H, s), 5.6 (1), 6.6 (1H, t), 7.1 (1H, t), 7.13(1H, t); m/z 237 (M+H)⁺

Methyl 3-[(phenylmethyl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

A mixture of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (18.8 g,72.75 mmol), (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (18.5 g,76.4 mmol) and potassium carbonate (20.08 g, 145.5 mmol) inbutyronitrile (250 mL) was heated to 130° C. for 3 hours. The solventwas removed in vacuo and ethyl acetate added. The organics were washedwith water (40 mL), 0.5M sodium hydroxide solution (40 mL), brine (40mL), dried (MgSO₄), filtered and the solvent removed in vacuo. Theresidue was chromatographed on silica, eluting with a gradient of 0-5%methanol in DCM, to give the desired compound as a colourless oil (20.1g). ¹H NMR δ (CDCl₃): 2.08-2.26 (m, 2H), 3.78-4.01 (m, 4H), 3.90 (s,3H), 4.92-4.96 (m, 1H), 5.08 (s, 2H), 6.69 (t, 1H), 7.15 (t, 1H), 7.29(t, 1H), 7.34-7.44 (m, 5H); m/z 327 (M+H)⁺

The preparations of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate and(3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate were describedearlier.

EXAMPLE 443-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(4-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.70 mL, 0.53 mmol) was addedto a solution of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid (200 mg, 0.48 mmol) in DCM (6 mL) and stirred at RT for 2 hours.2-Amino-4-methylthiazole (110 mg, 0.96 mmol) and pyridine (0.078 mL,0.96 mmol) were added and the reaction stirred at RT for 16 hours. Thesolvent was removed in vacuo, water (20 mL) added and the mixtureextracted with ethyl acetate (3×20 mL). The extracts were combined andwashed with 2N hydrochloric acid (20 mL), saturated aqueous sodiumbicarbonate solution (20 mL), water (20 mL), brine (20 mL), dried(MgSO₄), filtered, and evaporated in vacuo. The residue waschromatographed on silica, eluting with a gradient of 50-100% ethylacetate in isohexane, to give the desired compound (78 mg).

¹H NMR δ (CDCl₃): 2.13-2.28 (m, 2H), 2.31 (s, 3H), 2.35-2.43 (m, 2H),3.88-4.02 (m, 4H), 4.21-4.28 (m, 2H), 4.31-4.39 (m, 2H), 4.96-5.00 (m,1H), 6.56 (d, 1H), 6.94 (t, 1H), 7.28 (t, 1H), 7.34 (t, 1H), 8.16 (d,1H), 8.25 (d, 1H), 9.83 (s, 1H); m/z 515 (M+H)⁺, 513 (M−H)⁻

The following compounds were prepared in an analogous fashion from3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid and the appropriate aminoheterocycle.

Example Structure m/z NMR 44a

515(M + H)⁺513(M − H)⁻ ¹H NMR δ (CDCl₃): 2.13-2.29 (m, 2 H), 2.34-2.42(m, 2 H), 2.38 (s, 3 H), 3.88-4.02 (m, 4 H),4.24-4.34 (m, 4 H),4.96-4.99 (m, 1 H), 6.94(t, 1 H), 6.97 (d, 1 H), 7.34 (t, 1 H),7.36-7.37(m, 1 H), 8.15 (d, 1 H), 8.24 (d, 1 H), 10.82 (s,1 H) 44b

510(M + H)⁺508(M − H)⁻ ¹H NMR δ (CDCl₃): 2.15-2.31 (m, 2 H), 2.35-2.43(m, 2 H), 2.56 (s, 3 H), 3.89-4.03 (m, 4 H),4.20-4.39 (m, 4 H),4.99-5.03 (m, 1 H), 6.93(t, 1 H), 7.29 (t, 1 H), 7.35 (t, 1 H), 8.14 (s,1 H),8.16 (d, 1 H), 8.26 (d, 1 H), 8.36 (s, 1 H), 9.54(d, 1 H) 44c

512(M + H)⁺510(M − H)⁻ ¹H NMR δ (CDCl₃): 1.46 (t, 3 H), 2.14-2.30(m, 2H), 2.35-2.43 (m, 2 H), 3.88-4.02 (m,4 H), 4.06 (q, 2 H), 4.20-4.28 (m,2 H), 4.31-4.39 (m, 2 H), 4.97-5.01 (m, 1 H), 6.78 (d,1 H), 6.89 (t, 1H), 7.23 (t, 1 H), 7.30-7.31 (m,1 H), 7.32 (d, 1 H), 8.16 (d, 1 H), 8.25(d, 1 H),8.37 (s, 1 H) 44d

526(M + H)⁺524(M − H)⁻ ¹H NMR δ (CDCl₃): 1.48 (d, 6 H), 2.14-2.29(m, 2H), 2.35-2.43 (m, 2 H), 3.88-4.02 (m,4 H), 4.20-4.28 (m, 2 H), 4.30-4.40(m, 2 H),4.36 (septet, 1 H), 4.98-5.01 (m, 1 H), 6.78 (d,1 H), 6.89 (t,1 H), 7.24 (t, 1 H), 7.32 (t, 1 H),7.35 (d, 1 H), 8.16 (d, 1 H), 8.25(d, 1 H), 8.35(s, 1 H) 44e*

484(M + H)⁺482(M − H)⁻ ¹H NMR δ (CDCl₃): 2.12-2.29 (m, 2 H), 2.34-2.42(m, 2 H), 3.87-4.02 (m, 4 H), 4.20-4.28(m, 2 H), 4.29-4.37 (m, 2 H),4.97-5.00 (m,1 H), 6.85 (s, 1 H), 6.88 (t, 1 H), 7.29-7.30 (m,1 H),7.31-7.31 (m, 1 H), 7.44 (d, 1 H), 8.15 (d,1 H), 8.21 (d, 1 H), 9.76 (s,1 H), 10.17 (s, 1 H) *The reaction was carried out using1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate as the aminoheterocycle, the resultant product was dissolved in acetonitrile andheated in a microwave reactor at 150° C. for 5-10 minutes. The mixtureswere allowed to cool then concentrated in vacuo to give the desiredproducts. The preparation of 1,1-dimethylethyl3-amino-1H-pyrazole-1-carboxylate was described earlier. The preparationof3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid is described below:

3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid

Methyl3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate(3.75 g, 8.68 mmol) was dissolved in THF (40 mL), 1N sodium hydroxide(8.68 mL, 8.68 mmol) was added followed by water (40 mL) and methanol (1drop) and the resultant solution stirred at RT for 3 hours. The organicswere removed in vacuo, the aqueous solution filtered and extracted withethyl acetate (30 mL). The aqueous layer was acidified with 2Nhydrochloric acid, extracted with ethyl acetate (3×50 mL), and theorganic extracts washed with water (10 mL), brine (10 mL) thenevaporated to dryness to give the desired material as a white foam (3.53g).

¹H NMR δ (CDCl₃): 2.14-2.30 (m, 2H), 2.35-2.43 (m, 2H), 3.89-3.94 (m,2H), 3.96-4.02 (m, 2H), 4.22-4.38 (m, 4H), 4.97-5.01 (m, 1H), 6.95 (t,1H), 7.46-7.47 (m, 1H), 7.49-7.50 (m, 1H), 8.15 (d, 1H), 8.26 (d, 1H);m/z 419 (M+H)⁺, 417 (M−H)⁻.

Methyl3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

A solution of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate(2.5 g, 10.5 mmol), potassium carbonate (2.9 g, 21.0 mmol) and5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (2.9 g, 12.6 mmol) in DMA(25 mL) was heated at 120° C. for 5 hours. The solution was diluted withethyl acetate (150 mL), washed with water (3×50 mL), brine (20 mL),dried (MgSO₄), filtered and the solvent removed in vacuo. The residuewas purified by chromatography on silica, eluting with 20-50% ethylacetate in isohexane, to give the desired compound as a colourless oil(3.75 g). ¹H NMR δ (CDCl₃): 2.13-2.29 (m, 2H), 2.38 (quin, 2H),3.85-4.04 (m, 4H), 3.90 (s, 3H), 4.19-4.37 (m, 4H), 4.96-5.00 (m, 1H),6.91 (t, 1H), 7.42-7.45 (m, 2H), 8.14 (d, 1H), 8.25 (d, 1H); m/z 433(M+H)⁺.

The preparations of methyl3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate and5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine were described earlier.

EXAMPLE 453-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.133 mL, 1.0 mmol) was addedto a suspension of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid (350 mg, 0.94 mmol) in DCM (10 mL) and stirred at RT for 30 min.2-Amino-5-methylpyrazine (196 mg, 1.82 mmol) and pyridine (0.148 mL,1.82 mmol) were added and the reaction stirred at RT for 2 hours. Thesolvent was removed in vacuo and water (30 mL) added. The mixture wasextracted with ethyl acetate (3×20 mL), washed with 2N hydrochloric acid(20 mL), water (10 mL), saturated aqueous sodium bicarbonate solution(20 mL), water (10 mL) and brine (20 mL). The combined organic extractswere dried (MgSO₄), filtered and evaporated in vacuo. The residue waspurified by chromatography, eluting with 0-10% methanol in DCM, to givethe desired product as a colourless oil (150 mg). ¹H NMR δ (CDCl₃):2.12-2.18 (1H, m), 2.22-2.29 (1H, m), 2.31-2.40 (2H, m), 2.56 (3H, s),3.89-4.03 (4H, m), 4.25 (2H, t), 4.71 (2H, t), 4.97-5.00 (1H, m), 6.76(1H, t), 7.15 (1H, t), 7.25 (1H, d), 7.38-7.40 (1H, m), 8.12 (1H, s),8.14 (1H, d), 8.32 (1H, s), 8.34 (1H, d), 9.52 (1H, d); m/z 476 (M+H)⁺,474 (M−H)⁻

The following compound was prepared in an analogous fashion from3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid or3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid and the appropriate aminoheterocycle.

Example Structure m/z NMR 45a

477(M + H)⁺ ¹H NMR δ (CDCl₃): 2.16-2.31 (m, 2H), 2.34-2.42 (m, 2H), 2.56(s, 3H), 3.89-4.02 (M, 4H),4.26 (t, 2H), 4.69 (t, 2H), 4.98-5.02 (m,1H),6.92 (s, 1H), 7.30 (s, 1H), 7.35 (s, 1H), 8.15 (s,1H), 8.36 (s, 2H),8.86 (s, 1H), 9.54 (s, 1H) 45b

479(M + H)⁺477(M − H)⁻ ¹H NMR δ (CDCl₃): 2.12-2.31 (m, 2H), 2.32-2.40(m, 2H), 3.90-4.04 (m, 4H), 4.26 (t, 2H),4.71 (t, 2H), 4.97-5.01 (m,1H), 6.76 (t, 1H),7.13 (t, 1H), 7.23 (t, 1H), 7.39 (dd, 1H), 7.48-7.53(m, 1H), 8.14 (d, 1H), 8.16 (d, 1H), 8.33-8.38 (m, 2H), 8.47 (s, 1H) 45c

451(M + H)⁺449(M − H)⁻ ¹H NMR δ (CDCl₃): 2.13-2.31 (m, 2H), 2.32-2.39(m, 2H), 3.89-4.03 (m, 4H), 4.25 (t, 2H),4.71 (t, 2H), 4.97-5.01 (m,1H), 6.79 (t, 1H),7.18 (d, 1H), 7.22 (t, 1H), 7.27 (t, 1H), 7.37(dd,1H), 8.11 (d, 1H), 8.28 (d, 1H), 8.33 (d,1H), 9.47 (s, 1H) 45d

463(M + H)⁺461(M − H)⁻ ¹H NMR δ (CDCl₃): 2.15-2.32 (m, 2H), 2.35-2.43(m, 2H), 3.90-4.06 (m, 4H), 4.27 (t, 2H),4.70 (t, 2H), 5.00-5.05 (m,1H), 6.93 (t, 1H),7.31 (t, 1H), 7.36 (t, 1H), 8.29 (t, 1H), 8.38-8.38(m, 1H), 8.40-8.41 (m, 1H), 8.46 (s, 1H),8.86 (d, 1H), 9.68 (s, 1H) 45e

480(M + H)⁺478(M − H)⁻ ¹H NMR δ (CDCl₃): 2.15-2.31 (m, 2H), 2.35-2.43(m, 2H), 3.90-4.03 (m, 4H), 4.27 (t, 2H),4.69 (t, 2H), 4.99-5.02 (m,1H), 6.91 (t, 1H),7.28 (t, 1H), 7.33 (t, 1H), 7.48-7.53 (m, 1H),8.16 (d,1H), 8.35-8.39 (m, 1H), 8.37 (d, 1H),8.51 (s, 1H), 8.86 (d, 1H)

The preparation of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid was described earlier.

The preparation of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid is described below:

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid

Methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (875 mg, 3.68mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (1.06 g, 4.41 mmol),caesium carbonate (3.59 g, 11.03 mmol), andbromotris(triphenylphosphine)copper (0.69 g, 0.735 mmol) were addedtogether in DMA (16 mL) and heated in a microwave reactor at 160° C. for9 hours. The mixture was taken up in water (25 mL) and washed with ethylacetate (2×20 mL). The aqueous layer was acidified with 1N hydrochloricacid (30 mL) and extracted with ethyl acetate (5×30 mL). The combinedorganic extract was washed with water (30 mL), brine (30 mL), dried(MgSO₄), filtered and evaporated to give a brown solid which wastriturated with diethyl ether to give the desired compound as a beigesolid (820 mg).

¹H NMR δ (d₆-DMSO): 2.00-2.06 (m, 1H), 2.23-2.37 (m, 3H), 3.78-3.95 (m,4H), 4.13 (t, 2H), 4.64 (t, 2H), 5.16-5.19 (m, 1H), 7.05 (t, 1H),7.18-7.19 (m, 1H), 7.33-7.34 (m, 1H), 7.62 (dd, 1H), 8.04 (d, 1H), 8.46(d, 1H); m/z 385 (M+H)⁺, 383 (M−H)⁻

The preparations of methyl3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate and2-(azetidin-1-ylcarbonyl)-5-bromopyridine were described earlier.

EXAMPLE 463-{[3-Chloro-5-(pyrrolidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide

Cesium carbonate (782 mg, 2.4 mmol) was added to a solution of3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (230mg, 0.8 mmol) and 2,3-dichloro-5-(pyrrolidin-1-ylcarbonyl)pyridine (234mg, 0.96 mmol) in acetonitrile (5 mL) and the stirred mixture heated ina microwave reactor at 120° C. for 2 hours. The mixture was cooled to RTand the acetonitrile evaporated in vacuo. The residue was partitionedbetween water (25 mL) and ethyl acetate (50 mL), the organic layerwashed with brine, dried (MgSO₄) and evaporated to a residue which waschromatographed on silica, eluting with 75% ethyl acetate in isohexane,to give the desired compound (290 mg).

¹H NMR δ (CDCl₃): 1.3 (d, 6H), 1.9 (m, 4H), 2.5 (s, 3H), 3.4-3.7 (m,4H), 4.55 (m, 1H), 6.85 (d, 1H), 7.2 (d, 1H), 7.25 (d, 1H), 7.9 (d, 1H),8.1 (dd, 1H), 8.2 (s, 1H), 8.35 (s, 1H) and 9.45 (s, 1H); m/z 496(M+H)⁺.

The following compounds were prepared in an analogous fashion from2,3-dichloro-5-(pyrrolidin-1-ylcarbonyl)pyridine and either3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamideor3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide.

Example Structure m/z NMR 46a

526(M + H)⁺ ¹H NMR δ (CDCl₃): 1.3 (d, 3H), 1.9 (m, 4H),2.5 (s, 3H), 3.3(s, 3H), 3.4-3.6 (m, 6H), 4.55(m, 1H), 6.9 (d, 1H), 7.2 (s, 1H), 7.35(s, 1H),7.95 (d, 1H), 8.05 (s, 1H), 8.15 (d, 1H), 8.35(s, 1H), 9.5 (s,1H). 46b

512(M + H)⁺ ¹H NMR δ (CDCl₃): 1.8-1.95 (m, 4H), 2.1(m, 2H), 3.45 (t,2H), 3.6 (t, 2H), 3.7 (s, 3H),3.85 (m, 2H), 3.95 (d, 2H), 4.9 (m, 1H),6.7 (d,1H), 6.8 (d, 1H), 7.15 (d, 1H), 7.25 (d, 2H),7.95 (d, 1H), 8.1(d, 1H), 8.9 (s, 1H)

The preparation of 2,3-dichloro-5-(pyrrolidin-1-ylcarbonyl)pyridine isdescribed below:

2,3-Dichloro-5-(pyrrolidin-1-ylcarbonyl)pyridine

Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6dichloronicotinic acid (5.76 g; 30.0 mmol) and 4M hydrogen chloride indioxan (7.5 mL; 30.0 mmol) in DCM (50 mL). The mixture was stirred at RTfor 18 hours, the DCM evaporated in vacuo, the residue azeotroped withtoluene (2×15 mL) then added to a solution of pyrrolidine (3.0 mL; 36.0mmol) and triethylamine (10.0 mL; 72 mmol) in DCM (150 mL). The mixturewas stirred at RT for 6 hours, the DCM evaporated in vacuo, the residuepartitioned between water (75 mL) and ethyl acetate (100 mL), theorganic layer washed with brine, dried (MgSO₄) and evaporated in vacuo.The residue was chromatographed on silica, eluting with 50% ethylacetate in isohexane, to give the desired compound which was furtherpurified by crystallisation from ethyl acetate and isohexane (6.88 g).¹H NMR δ (CDCl₃): 1.9 (m, 4H), 3.4 (m, 2H), 3.6 (s, 3H), 7.9 (s, 1H) and8.4 (s, 1H); m/z 245 (M+H)⁺.

The preparations of3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide and3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamidewere described earlier.

EXAMPLE 473-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

3-Hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide(209 mg, 0.66 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (159 mg,0.80 mmol) and potassium carbonate (184 mg, 1.33 mmol) weredissolved/suspended in acetonitrile (3.5 mL). The reaction mixture washeated in a microwave reactor for 4 hours at 120° C. then cooled,filtered and reduced in vacuo. The crude product was purified bychromatography on silica, eluting with 0-5% methanol in DCM, to give therequired product as a white foam (39 mg). ¹H NMR δ (d₆-DMSO): 1.57-1.68(m, 2H), 1.97-2.05 (m, 2H), 2.26-2.36 (m, 2H), 3.47-3.55 (m, 2H), 3.78(s, 3H), 3.84-3.91 (m, 2H), 4.10 (t, 2H), 4.57 (t, 2H), 4.67-4.75 (m,1H), 6.58 (d, 1H), 7.11 (t, 1H), 7.43 (t, 1H), 7.54 (t, 1H), 7.60 (d,1H), 8.56 (d, 1H), 8.68 (d, 1H), 10.80 (s, 1H); m/z 479 (M+H)⁺

The following compounds were made in an analogous fashion from theeither3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamideor3-hydroxy-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamideand the appropriate halogenated heterocycle.

Example Structure m/z NMR 47a

512(M + H)⁺ ¹H NMR δ (d₆-DMSO): 1.57-1.67 (m, 2H),1.98-2.06 (m, 2H),2.21-2.32 (m, 2H), 3.47-3.55 (m, 2H), 3.78 (s, 3H), 3.84-3.91 (m,2H),4.01-4.10 (m, 2H), 4.33-4.41 (m, 2H), 4.67-4.75 (m, 1H), 6.57 (d,1H), 7.09 (t, 1H), 7.40 (t,1H), 7.52 (t, 1H), 7.60 (d, 1H), 8.23 (d,1H),8.34 (d, 1H), 10.79 (s, 1H) 47b

491(M + H)⁺ ¹H NMR δ (d₆-DMSO): 1.58-1.68 (m, 2H),1.99-2.06 (m, 2H),2.26-2.35 (m, 2H), 2.49 (s,3H), 3.47-3.55 (m, 2H), 3.84-3.91 (m,2H),4.10 (t, 2H), 4.57 (t, 2H), 4.69-4.77 (m, 1H),7.18 (t, 1H), 7.49 (t,1H), 7.58 (t, 1H), 8.36 (d,1H), 8.57 (d, 1H), 8.68 (d, 1H), 9.25 (d,1H),10.98 (s, 1H) 47c

524(M + H)⁺ ¹H NMR δ (d₆-DMSO): 1.63 (m, 2H), 2.02 (m,2H), 2.27 (m, 2H),2.49 (s, 3H), 3.51 (m, 2H),3.87 (m, 2H), 4.06 (t, 2H), 4.36 (t, 2H),4.74 (m,1H), 7.16 (t, 1H), 7.47 (t, 1H), 7.57 (t, 1H), 8.23(d, 1H), 8.34(d, 1H), 8.36 (m, 1H), 9.25 (d, 1H),10.98 (s, 1H)

The preparations of 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine and5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine were described earlier.

The preparation of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamideis described below:

3-Hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxybenzamide

N-(1-Methyl-1H-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide(1.85 g, 4.54 mmol) was dissolved in ethanol (40 mL) and 10% palladiumon charcoal (97 mg) catalyst added under argon. The reaction was stirredunder an atmosphere of hydrogen for 16 hours then filtered throughCelite® and the filtrate concentrated in vacuo give the desired compoundas a light brown solid (1.30 g).

¹H NMR δ (d₆-DMSO): 1.54-1.65 (m, 2H), 1.94-2.03 (m, 2H), 3.44-3.54 (m,2H), 3.78 (s, 3H), 3.83-3.90 (m, 2H), 4.56-4.65 (m, 1H), 6.51 (t, 1H),6.56 (d, 1H), 6.97 (t, 1H), 7.08 (t, 1H), 7.59 (d, 1H), 9.63 (s, 1H),10.59 (s, 1H); m/z 318 (M+H)⁺

N-(1-Methyl-1H-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

3-[(Phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid (3.14g, 9.5 mmol), 1-methyl-1H-pyrazol-3-amine (1.85 g, 19.0 mmol) and HATU(4.70 g, 12.35 mmol) were dissolved in DMF (12.5 mL) and DIPEA (3.31 mL,19.0 mmol) added. The resultant mixture was stirred at RT for 20 hours.The mixture was quenched with water (150 mL), extracted with ethylacetate (2×75 mL), washed with brine, dried (MgSO₄) and concentrated invacuo. The residue was chromatographed on silica, eluting with 0-50%ethyl acetate in isohexane, to give the desired compound as a paleyellow gum (1.85 g).

3-[(Phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid

Methyl 3-[(phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoate(9.00 g, 26.3 mmol) was dissolved in THF (120 mL) and methanol (30 mL)added a solution of lithium hydroxide monohydrate (3.24 g, 78.9 mmol) inwater (60 mL). The bi-phasic solution was stirred at RT for 3 hoursuntil complete conversion was indicated by LCMS. The organics wereremoved in vacuo and water (40 mL) added. The pH of the mixture wasadjusted to 7 by the addition of hydrochloric acid and the resultingprecipitate filtered and washed with cold water to give the desiredcompound as a white solid (8.03 g). ¹H NMR δ (d₆-DMSO): 1.57 (m, 2H),1.94 (m, 2H), 3.50 (m, 2H), 3.84 (m, 2H), 4.62 (m, 1H), 5.15 (s, 2H),6.87 (t, 1H), 7.09 (m, 1H), 7.14 (m, 1H), 7.34 (t, 1H), 7.40 (t, 2H),7.46 (d, 2H), 12.99 (s, 1H); m/z 327 (M+H)⁺

Methyl 3-[(phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy benzoate

Methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (7.75 g, 30.0 mmol),tetrahydro-4H-pyra-4-ol (4.28 mL, 45.0 mmol) and triphenylphosphine(11.8 g, 45.0 mmol) were stirred under argon in THF (166 mL) and cooledto 5° C. in an ice bath. DEAD (19.6 mL, 45.0 mmol) was added dropwise tothe mixture, maintaining the internal temperature below 10° C. Stirringwas continued for 16 hours then the reaction mixture reduced in vacuoand the residue redissolved in ethyl acetate (60 mL) and isohexane (60mL). The precipitate was removed, the filtrate concentrated in vacuo andpurified by chromatography on silica, eluting with 0-25% ethyl acetatein isohexane (a small quantity of DCM used to assist column loading), togive the desired compound as a colourless oil (9.0 g).

¹H NMR 5 (d₆-DMSO): 1.58 (m, 2H), 1.94 (m, 2H), 3.49 (m, 2H), 3.84 (m,5H), 4.65 (m, 1H), 5.16 (s, 2H), 6.92 (t, 1H), 7.10 (m, 1H), 7.15 (m,1H), 7.34 (t, 1H), 7.40 (t, 2H), 7.46 (d, 2H); m/z 343 (M+H)⁺

The preparation of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate wasdescribed earlier. The preparation of3-hydroxy-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamideis described below:

3-Hydroxy-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pryan-4-yloxy)benzamide

N-(5-Methylpyrazin-2-yl)-3-[(phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide(1.70 g, 4.05 mmol) was dissolved in ethanol (40 mL) and 10% palladiumon charcoal (86 mg) catalyst added under argon. The reaction was stirredunder 1.26 mmol) were dissolved/suspended in DMA (3.5 mL). The reactionmixture was heated in a microwave reactor for 1 hour at 200° C. thenallowed to cool, filtered and reduced in vacuo. Water (25 mL) was addedand the product extracted with ethyl acetate (2×25 mL), the organicsdried (MgSO₄) then purified by chromatography on silica, eluting with0-10% methanol in DCM, to give the desired compound as a pale yellowfoam (65 mg). ¹H NMR 8 (d₆-DMSO): 1.57-1.67 (m, 2H), 1.97-2.05 (m, 2H),2.23-2.34 (m, 2H), 3.51 (t, 2H), 3.78 (s, 3H), 3.83-3.90 (m, 2H), 4.08(t, 2H), 4.59 (t, 2H), 4.69-4.76 (m, 1H), 6.56 (d, 1H), 7.00 (t, 1H),7.29 (t, 1H), 7.49 (t, 1H), 7.54-7.58 (m, 1H), 7.60 (d, 1H), 8.00 (d,1H), 8.41 (d, 1H), 10.83 (s, 1H); m/z 478 (M+H)⁺

The following compound was made in an analogous fashion from2-(azetidin-1-ylcarbonyl)-5-bromopyridine and3-hydroxy-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide.

Example Structure m/z NMR 48a

490(M + H)⁺ ¹H NMR δ (d₆-DMSO): 1.62 (m, 2H), 2.01(m, 2H), 2.28 (m, 2H),2.48 (s, 3H), 3.50 (m,2H), 3.86 (m, 2H), 4.07 (t, 2H), 4.59 (t, 2H),4.75(m, 1H), 7.08 (t, 1H), 7.49 (s, 1H), 7.53(s, 1H), 7.56 (q, 1H), 8.00 (d,1H), 8.36 (s,1H), 8.43 (d, 1H), 9.24 (d, 1H), 11.09 (s,1H)

The preparations of 2-(azetidin-1-ylcarbonyl)-5-bromopyridine,3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamideand3-hydroxy-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamidewere described earlier.

EXAMPLE 493-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

A mixture of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide(150 mg, 0.49 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (120 mg,0.49 mmol), bromotris(triphenylphosphine)copper (92 mg, 0.10 mmol) andcaesium carbonate (484 mg, 1.48 mmol) in acetonitrile (7 mL) was stirredin a microwave reactor at 160° C. for 6 hours. The solid was filteredoff, the solvent was removed in vacuo and ethyl acetate (50 mL) added tothe residue. The organic phase was washed with water (10 mL), brine (20mL), dried (MgSO₄), filtered and the solvent removed in vacuo. Theresidue was chromatographed on silica, eluting with a gradient of 0-10%methanol in DCM, to give the title compound as a white solid (86 mg). ¹HNMR δ (CDCl₃): 2.10-2.17 (m, 1H), 2.19-2.25 (m, 1H), 2.32-2.38 (m, 2H),3.76 (s, 3H), 3.87-3.92 (m, 1H), 3.95-4.01 (m, 3H), 4.24 (t, 2H), 4.71(t, 2H), 4.97 (t, 1H), 6.73 (t, 1H), 6.81 (s, 1H), 7.11 (s, 1H), 7.24(s, 1H), 7.27-7.30 (m, 1H), 7.36-7.39 (m, 1H), 8.12 (d, 1H), 8.31 (d,1H), 8.72 (s, 1H); m/z 464 (M+H)⁺.

The preparation of 2-(azetidin-1-ylcarbonyl)-5-bromopyridine wasdescribed earlier. The preparation of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamideis described below:

3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

A suspension of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide(450 mg, 1.39 mmol), (3S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate(507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 an atmosphereof hydrogen for 4 days then filtered and the filtrate concentrated invacuo to give the desired compound as a cream-coloured solid (1.20 g).m/z 330 (M+H)⁺

N-(5-Methylpyrazin-2-yl)-3-[(phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

3-[(Phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid (3.14g, 9.5 mmol), 2-amino-5 methylpyrazine (2.08 g, 19.0 mmol) and HATU(4.70 g, 12.35 mmol) were dissolved in DMF (12.5 mL) and DIPEA (3.31 mL,19.0 mmol) added. The resultant mixture was stirred at RT for 20 hours.The mixture was quenched with water (150 mL) and extracted with ethylacetate (2×75 mL), washed with brine, dried (MgSO₄) and concentrated invacuo. The residue was chromatographed on silica, eluting with 0-50%ethyl acetate in isohexane, to give the desired compound as a paleyellow gum (1.70 g).

m/z 420 (M+H)⁺

The preparations of3-[(phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid and2-amino-5 methylpyrazine were described earlier.

EXAMPLE 483-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

3-Hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide(200 mg, 0.63 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (184 mg,0.76 mmol), bromotris(triphenylphosphine)copper (186 mg, 0.2 mmol) andcaesium carbonate (411 mg, mmol) in acetonitrile (5 mL) was stirred in amicrowave reactor at 160° C. for 3 hours. The solvent was removed invacuo and ethyl acetate added. The organics were washed with water (40mL), brine (40 mL), dried (MgSO₄), filtered and the solvent removed invacuo. The residue was chromatographed on silica, eluting with agradient of 0-100% ethyl acetate in isohexane, to giveN-(1-methyl-1H-pyrazol-3-yl)-3-[(phenylmethyl)oxy]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamideas a white foam. This was dissolved in ethanol (5 mL) and ammoniumformate (182 mg, 2.88 mmol) added in one portion. The reaction wasblanketed with argon and 10% palladium on activated carbon (30 mg) wasadded. This mixture was heated in a microwave reactor at 140° C. for 10minutes, the catalyst filtered off and the volatiles removed in vacuo togive the title product as a white solid (305 mg).

¹H NMR δ (d₆-DMSO): 1.96-2.00 (m, 1H), 2.20-2.25 (m, 1H), 3.74-3.85 (m,6H), 3.87-3.91 (m, 1H), 5.06-5.08 (m, 1H), 6.46 (t, 1H), 6.57 (d, 1H),6.97 (s, 1H), 7.02 (s, 1H), 7.60 (d, 1H), 9.74 (s, 1H), 10.70 (s, 1H);m/z 304 (M+H)⁺.

The preparation of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamidewas described earlier. (3S)-Tetrahydrofuran-3-yl4-methylbenzenesulfonate was prepared in an analogous fashion to(3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate, as described inExample 25.

EXAMPLE 503-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyridin-2-ylbenzamide

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.080 mL, 0.6 mmol) was addedto a solution of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid (193 mg, 0.50 mmol) in DCM (10 mL) and stirred at RT for 30minutes. 2-Aminopyridine (57 mg, 0.6 mmol) and pyridine (0.082 mL, 1mmol) were added and the reaction stirred for a further 16 hours. Thesolvent was removed in vacuo and the residue was taken up in ethylacetate (50 mL). The organic phase was washed with water (2×20 mL), 1Ncitric acid (10 mL), water (10 mL), a saturated aqueous solution ofsodium bicarbonate (10 mL) and brine (100 mL), then dried (MgSO₄),filtered, and evaporated in vacuo. The residue was chromatographed onsilica, eluting with a gradient of 50-80% ethyl acetate in isohexane, togive the desired compound as a white foam (42 mg). ¹H NMR δ (CDCl₃):1.28 (d, 3H), 2.31 (quin, 2H), 3.34 (s, 3H), 3.43-3.56 (m, 2H), 4.19 (t,2H), 4.57 (q, 1H), 4.62 (t, 2H), 6.90 (s, 1H), 7.03 (t, 1H), 7.20 (s,1H), 7.36 (s, 1H), 7.71 (t, 1H), 8.23 (d, 1H), 8.28 (s, 1H), 8.30 (d,1H), 8.64 (s, 1H), 8.79 (s, 1H); m/z 464 (M+H)⁺

The following compounds were prepared in an analogous fashion from theappropriate benzoic acid and the appropriate aminoheterocycle.

Example Structure m/z NMR 50a

454(M + H)⁺ ¹H NMR δ (CDCl₃): 1.27 (d, 3H), 2.26-2.38(m, 2H), 3.34 (s,3H), 3.42-3.57 (m, 2H), 4.19(t, 2H), 4.51-4.70 (m, 3H), 6.92 (s, 1H),7.12(s, 1H), 7.27 (s, 1H), 7.36 (s, 1H), 8.20 (s, 1H),8.27 (s, 1H), 8.78(s, 1H), 9.33 (s, 1H) 50b

484(M + H)⁺ ¹H NMR δ (CDCl₃): 1.26 (d, 3H), 2.22 (s, 3H),2.27-2.39 (m,2H), 3.33 (s, 3H), 3.41-3.57(m, 2H), 4.19 (t, 2H), 4.50-4.58 (m, 1H),4.62(t, 2H), 6.50 (s, 1H), 6.92 (s, 1H), 7.23 (s, 1H),7.35 (s, 1H), 8.27(s, 1H), 8.78 (s, 1H) 50c

484(M + H)⁺ ¹H NMR δ (CDCl₃): 1.26 (d, 3H), 2.25-2.36(m, 5H), 3.32 (s,3H), 3.40-3.54 (m, 2H), 4.19(t, 2H), 4.52 (q, 1H), 4.61 (t, 2H), 6.81(s, 1H),6.92 (s, 1H), 7.28 (s, 1H), 7.38 (s, 1H), 8.25 (s,1H), 8.77 (s,1H) 50d

465(M + H)⁺ ¹H NMR δ (CDCl₃): 1.29 (d, 3H), 2.32 (quin,2H), 3.34 (s,3H), 3.44-3.56 (m, 2H), 4.19 (t,2H), 4.56 (q, 1H), 4.62 (t, 2H), 6.92(s, 1H),7.23 (s, 1H), 7.35 (s, 1H), 8.21 (s, 1H), 8.29 (s,1H), 8.33 (s,1H), 8.43 (s, 1H), 8.79 (s, 1H),9.61 (s, 1H) 50e

435(M + H)⁺ ¹H NMR δ (CDCl₃): 1.31 (d, 6H), 2.32 (quin,2H), 4.19 (t,2H), 4.56 (quin, 1H), 4.62 (t, 2H),6.85 (s, 1H), 7.20 (s, 1H), 7.30 (s,1H), 8.21 (s,1H), 8.29 (s, 1H), 8.33 (s, 1H), 8.40 (s, 1H),8.80 (s, 1H),9.61 (s, 1H) 50f

464(M+ H)⁺ ¹H NMR δ (CDCl₃): 1.27 (d, 3H), 2.29 (quin,2H), 3.34 (s, 3H),3.43-3.55 (m, 2H), 4.18 (t,2H), 4.56 (q, 1H), 4.64 (t, 2H), 6.78 (s,1H),7.09 (s, 1H), 7.26 (s, 1H), 7.32 (d, 1H), 8.06(d, 1H), 8.22 (s, 1H),8.27 (s, 1H), 8.34 (s, 1H),8.36 (s, 1H), 9.60 (s, 1H) 50g*

468(M+ H)⁺ ¹H NMR δ (CDCl₃): 1.31 (d, 6H), 2.32 (quin,2H), 4.17 (t, 2H),4.29 (t, 2H), 4.57 (quin, 1H),6.87 (s, 1H), 7.20 (s, 1H), 7.29 (s, 1H),8.10 (s,1H), 8.19 (s, 1H), 8.21 (s, 1H), 8.32 (s, 1H),8.42 (s, 1H), 9.62(s, 1H) 50h

498(M+ H)⁺ ¹H NMR δ (CDCl₃): 1.29 (d, 3H), 2.32 (quin,2H), 3.35 (s, 3H),3.43-3.57 (m, 2H), 4.17 (t,2H), 4.29 (t, 2H), 4.57 (q, 1H), 6.93 (s,1H),7.24 (s, 1H), 7.35 (s, 1H), 8.10 (s, 1H), 8.19 (s,1H), 8.21 (s, 1H),8.32 (s, 1H), 8.42 (s, 1H),9.62 (s, 1H) ^(*)The isolated sample wascontaminated with approximately 15% of an unknown impurity followinginitial chromatography.

The preparations of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid,3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]benzoicacid,3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid,3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]benzoicacid, and3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid were described earlier.

EXAMPLE 513-{[3-Chloro-5-(morpholin-4-ylcarbonyl)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide(152 mg, 0.5 mmol) and 4-[(5,6-dichloropyridin-3-yl)carbonyl]morpholine(143 mg, 0.55 mmol) in acetonitrile (5 mL) and the mixture heated at120° C. in a microwave reactor for 2 hours. The acetonitrile wasevaporated in vacuo and the residue partitioned between water (25 mL)and ethyl acetate (50 mL). The organic layer was washed with brine,dried (MgSO₄) and evaporated to a residue which was chromatographed onsilica, eluting with ethyl acetate, to give the desired compound (203mg). ¹H NMR δ (CDCl₃): 2.05-2.2 (m, 2H), 3.4-3.7 (m, 8H), 3.7 (s, 3H),3.85 (m, 2H), 3.95 (d, 2H), 4.9 (m, 1H), 6.7 (d, 1H), 6.8 (d, 1H), 7.15(d, 1H), 7.25 (d, 2H), 7.85 (d, 1H), 8.0 (d, 1H), 8.95 (s, 1H); m/z 512(M+H)⁺.

The following compound was prepared in an analogous fashion from3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamideand 7-[(5,6-dichloropyridin-3-yl)carbonyl]-7-azabicyclo[2.2.1]heptane

Example Structure m/z NMR 51a

538(M + H)⁺ ¹H NMR δ (CDCl₃): 1.5 (m, 4H), 1.7-1.9(m, 4H), 2.05-2.2 (m,2H), 3.7 (s, 3H),3.85 (m, 2H), 3.95 (d, 2H), 4.1 (m, 1H),4.7 (m, 1H),4.9 (m, 1H), 6.75 (d, 1H),6.85 (d, 1H), 7.2 (d, 1H), 7.25 (d, 2H),8.0(d, 1H), 8.2 (d, 1H) and 9.0 (s, 1H).

The preparation of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamidewas described earlier.

The preparation of 4-[(5,6-dichloropyridin-3-yl)carbonyl]morpholine isdescribed below:

4-[(5 6-Dichloropyridin-3-yl)carbonyl]morpholine

Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6dichloronicotinic acid (5.76 g; 30.0 mmol) and 4M hydrogen chloride indioxane (7.5 mL; 30 mmol) in DCM (50 mL). The mixture was stirred at RTfor 18 hours, the DCM evaporated in vacuo, the residue azeotroped withtoluene (2×15 mL) and added to a solution of morpholine (3.1 mL; 36.0mmol) and triethylamine (10.0 mL; 72 mmol) in DCM (150 mL). The mixturewas stirred at RT for 18 hours, the DCM evaporated in vacuo, and theresidue partitioned between water (75 mL) and ethyl acetate (100 mL).The organic layer was washed with brine, dried (MgSO₄) and evaporated toa residue which was chromatographed on silica, eluting with 50% ethylacetate in isohexane, to give the desired compound (7.1 g).

¹H NMR δ (CDCl₃): 3.3-3.8 (br, 8H), 7.8 (s, 1H), 8.25 (s, 1H); m/z 261(M+H)⁺.

The preparation of7-[(5,6-dichloropyridin-3-yl)carbonyl]-7-azabicyclo[2.2.1]heptane isdescribed below:

7-[(5,6-Dichloropyridin-3-yl)carbonyl]-7-azabicyclo[2.2.1]heptane

Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6dichloronicotinic acid (5.76 g, 30.0 mmol) and 4M hydrogen chloride indioxane (7.5 mL; 30.0 mmol) in DCM (50 mL). The mixture was stirred atRT for 18 hours, the DCM evaporated in vacuo, the residue azeotropedwith toluene (2×15 mL) and added to a solution of7-azabicyclo[2.2.1]heptane hydrochloride (4.75 g; 36.0 mmol) andtriethylamine (15.1 mL; 108 mmol) in DCM (150 mL). The mixture wasstirred at RT for 18 hours, the DCM evaporated in vacuo and the residuepartitioned between water (75 mL) and ethyl acetate (150 mL). Theorganic layer was washed with brine, dried (MgSO₄) and evaporated togive a solid which was crystallised from ethyl acetate to give thedesired compound (5.45 g).

¹H NMR δ (CDCl₃): 1.5 (m, 4H), 1.85 (m, 4H), 4.0 (br, 1H), 4.65 (br,1H), 7.9 (s, 1H), 8.4 (s, 1H); m/z 271 (M+H)⁺.

EXAMPLE 523-{[5-(Azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide(152 mg, 0.5 mmol) and5-(azetidin-1-ylcarbonyl)-2-bromo-4-methyl-1,3-thiazole (144 mg, 0.55mmol) in acetonitrile (5 mL) and the stirred mixture heated at 120° C.in a microwave reactor for 2 hours. The mixture was allowed to cool, theacetonitrile evaporated in vacuo, and the residue partitioned betweenwater (25 mL) and ethyl acetate (50 mL). The organic layer was washedwith brine, dried (MgSO₄) and evaporated to a residue which waschromatographed on silica, eluting with ethyl acetate, to give thedesired compound as a solid which was further crystallised from an ethylacetate/isohexane mixture (122 mg).

¹H NMR δ (CDCl₃): 2.0-2.15 (m, 2H), 2.2-2.3 (m, 2H), 2.5 (s, 3H), 3.75(s, 3H), 3.85 (m, 2H), 3.95 (d, 2H), 4.1-4.3 (m, 4H), 4.9 (m, 1H), 6.75(d, 1H), 6.95 (d, 1H), 7.25 (d, 2H), 7.3 (d, 1H) and 8.8 (s, 1H); m/z484 (M+H)⁺.

The preparations of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamideand 5-(azetidin-1-ylcarbonyl)-2-bromo-4-methyl-1,3-thiazole weredescribed earlier.

EXAMPLE 533-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

1M Hydrochloric acid (5 mL) was added to a solution of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide(82 mg, 0.14 mmol) in methanol (5 mL) and stirred at RT for 1 hour. Themethanol was removed in vacuo and the residue taken to pH6, extractedinto ethyl acetate (3×50 mL) and the combined organics washed with brine(50 mL), dried (MgSO₄), filtered and reduced in vacuo. The crude yellowoil was chromatographed on silica, eluting with 0-5% methanol in ethylacetate, to give the desired compound as a white foam (36 mg). Thecompound could be crystallised from a mixture of tert-butylmethyl etherand methanol. ¹H NMR δ (CDCl₃): 1.24 (d, 3H), 1.81 (s, 1H), 2.28 (quin,2H), 2.48 (s, 3H), 3.67-3.72 (m, 2H), 4.17 (t, 2H), 4.47-4.54 (m, 1H),4.63 (t, 2H), 6.73 (t, 1H), 7.09 (t, 1H), 7.25 (t, 1H), 7.27-7.30 (m,1H), 8.01-8.06 (m, 2H), 8.24 (d, 1H), 8.58 (s, 1H), 9.44 (d, 1H); m/z464 (M+H)⁺

The following compound was synthesised in an analogous fashion from3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide.

Example Structure m/z NMR 53a

470(M + H)⁺ ¹H NMR δ (CDCl₃): 1.22 (d, 3H), 2.28(quin, 2H), 2.40 (s,3H), 3.00 (s, 1H), 3.70(d, 2H), 4.16 (t, 2H), 4.51 (sextet, 1H),4.64 (t,2H), 6.74 (t, 1H), 7.20-7.27 (m,3H), 7.97 (d, 1H), 8.23 (d, 1H), 11.55(s,1H)

The preparation of 3-{[6-(azetidin1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamideis described below.

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.11 mL, 0.80 mmol) was addedto a solution of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoicacid (0.3 g, 0.62 mmol) in DCM (10 mL) and stirred for 1 hour.2-Amino-5-methylpyrazine (135 mg, 1.23 mmol), then pyridine (0.1 mL,1.23 mmol), were added and the mixture stirred for a further 30 minsbefore being reduced in vacuo and partitioned between ethyl acetate (50mL) and water (50 mL). The aqueous layer was further extracted intoethyl acetate (50 mL) and the combined organics washed with water (50mL), brine (50 mL), dried (MgSO₄), filtered and reduced in vacuo. Thecrude oil was chromatographed on silica, eluting with 40-100% ethylacetate in isohexane, to give the desired compound as a colourless oil(82 mg).

¹H NMR δ (CDCl₃): 0.00 (s, 3H), 0.03 (s, 3H), 0.83 (s, 9H), 1.28 (d,3H), 2.32 (quin, 2H), 2.53 (s, 3H), 3.64-3.77 (m, 2H), 4.22 (t, 2H),4.47-4.51 (m, 1H), 4.68 (t, 2H), 6.81 (t, 1H), 7.10 (t, 1H), 7.27 (t,1H), 7.33-7.35 (m, 1H), 8.08-8.11 (m, 2H), 8.30 (d, 1H), 8.37 (s, 1H),9.50 (d, 1H); m/z 578 (M+H)⁺

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamidewas prepared in an analogous fashion from3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoicacid.

Structure m/z

584(M + H)⁺

The preparation of 2-amino-5-methylpyrazine was described earlier.

The preparation of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoicacid is described below.

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoicacid

tert-Butyldimethylsilyl chloride (1.11 g, 7.36 mmol) was added to amixture of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoicacid (1.37 g, 3.68 mmol) and 1,8-diazabicyclo(5,4,0)undec-7-ene (1.11mL, 7.36 mmol) in acetonitrile (20 mL) and stirred at RT for 24 hours.The solvent was removed in vacuo and water (80 mL) added to theresultant oil. The mixture was adjusted to pH 10 with 1M sodiumbicarbonate solution then washed with ether (80 mL) to removeimpurities. The aqueous layer was adjusted to pH 3 with 1M citric acidand extracted into ethyl acetate (2×100 mL) and the combined organicswashed with brine (50 mL), dried (MgSO₄), filtered and reduced in vacuo.The crude material was chromatographed on an Isolute NH2 cartridge,eluting with methanol then ammonia in methanol, to give a beige foam.This material was subsequently triturated with ethyl acetate to give thedesired compound as a beige foam (1.0 g). ¹H NMR δ (CDCl₃): 0.01 (s,3H), 0.03 (s, 3H), 0.83 (s, 9H), 1.27 (d, 3H), 2.26-2.35 (m, 2H),3.58-3.79 (m, 2H), 4.15-4.25 (m, 2H), 4.43-4.49 (m, 1H), 4.60-4.69 (m,2H), 6.77-6.82 (m, 1H), 7.28 (m, 2H), 7.42-7.44 (m, 1H), 8.02-8.07 (m,1H), 8.27-8.29 (m, 1H); m/z 487 (M+H)⁺

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoicacid

A mixture of methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate(2.35 g, 10.39 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (2.51 g,10.39 mmol), cesium carbonate (10.16 g, 31.16 mmol) andbromotris(triphenylphosphine)copper (1.93 g, 2.08 mmol) in DMA (20 mL)was stirred in a microwave reactor at 160° C. for 8 hours. The mixturewas partitioned between ethyl acetate (50 mL) and water (50 mL). Theaqueous layer was acidified with 1M citric acid and extracted into ethylacetate (2×100 mL), washed with brine, dried (MgSO₄) and the solventremoved in vacuo. The crude oil was chromatographed on an Isolute NH2cartridge, eluting with methanol then ammonia in methanol, to give thedesired material as a beige foam (1.37 g). m/z 373 (M+H)⁺

The preparations of methyl3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate and2-(azetidin-1-ylcarbonyl)-5-bromopyridine were described earlier.

EXAMPLE 543-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

1M Hydrochloric acid (10 mL) was added to a solution of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide(180 mg, 0.29 mmol) in methanol (10 mL) and stirred at RT for 1 hour.The methanol was removed in vacuo and the residue adjusted to pH 6 thenextracted into ethyl acetate (3×50 mL). The combined organics werewashed with brine (50 mL), dried (MgSO₄), and reduced in vacuo to give ayellow oil which was chromatographed on silica, eluting with 0-5%methanol in ethyl acetate, to give the desired compound as a white foam(134 mg). The compound was crystallised from ethyl acetate and methanol.

¹H NMR δ (CDCl₃): 1.33 (d, 3H), 2.40 (quin, 2H), 2.56 (s, 3H), 3.76-3.81(m, 2H), 4.25 (t, 2H), 4.38 (t, 2H), 4.57-4.64 (m, 1H), 6.98 (t, 1H),7.31 (t, 1H), 7.42 (t, 1H), 8.14 (s, 1H), 8.17 (d, 1H), 8.26 (d, 1H),8.64 (s, 1H), 9.55 (s, 1H); m/z 498 (M+H)⁺

The following compounds were prepared in an analogous fashion:

Example Structure m/z NMR 54a

504(M + H)⁺ ¹H NMR δ (CDCl₃): 1.30 (d, 3H), 2.40 (quin,2H), 2.47 (s,3H), 3.23 (s, 1H), 3.78-3.79 (m,2H), 4.25 (t, 2H), 4.38 (t, 2H), 4.58(sextet,1H), 6.97 (t, 1H), 7.39-7.40 (m, 2H), 8.15 (d,1H), 8.22 (d, 1H),11.68 (s, 1H) 54b

484(M + H)⁺ ¹H NMR δ (CDCl₃): 1.27 (d, 3H), 2.02 (t,1H), 2.33 (quin,2H), 3.70-3.73 (m, 2H),4.17 (t, 2H), 4.30 (t, 2H), 4.52-4.56 (m,1H),6.93 (t, 1H), 7.24 (t, 1H), 7.35 (t, 1H), 8.10 (d,1H), 8.19 (d, 1H),8.21-8.22 (m, 1H), 8.33(d, 1H), 8.43 (s, 1H), 9.61 (d, 1H) 54c

483(M + H)⁺ ¹H NMR δ (CDCl₃): 1.26 (d, 3H), 2.17 (t,1H), 2.32 (quin,2H), 3.67-3.74 (m, 2H),4.17 (t, 2H), 4.30 (t, 2H), 4.49-4.56 (m,1H),6.89 (t, 1H), 7.00-7.03 (m, 1H), 7.23 (t, 1H),7.34 (t, 1H),7.67-7.71 (m, 1H), 8.10 (d, 1H),8.18 (d, 1H), 8.22-8.23 (m, 1H), 8.28(d,1H), 8.54 (s, 1H)

The preparation of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamideis described below.

3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.1 mL, 0.75 mmol) was addedto a solution of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoicacid (0.3 g, 0.58 mmol) in DCM (10 mL) and stirred for 1 hour.2-Amino-5-methylpyrazine (126 mg, 1.15 mmol) then pyridine (0.094 mL,1.15 mmol) were added and the mixture stirred for a further 30 minsbefore being reduced in vacuo and partitioned between ethyl acetate (50mL) and water (50 mL). The aqueous layer was further extracted intoethyl acetate (50 mL) and the combined organics washed with water (50mL), brine (50 mL), dried (MgSO₄), and reduced in vacuo. The crude oilwas chromatographed on silica, eluting with 40-100% ethyl acetate inisohexane, to give the title compound as an oil (180 mg).

¹H NMR δ (CDCl₃): 0.00 (s, 3H), 0.03 (s, 3H), 0.82 (s, 9H), 1.28 (d,3H), 2.35 (quin, 2H), 2.51 (s, 3H), 3.63-3.78 (m, 2H), 4.19 (t, 2H),4.32 (t, 2H), 4.47-4.51 (m, 1H), 6.95 (t, 1H), 7.23-7.24 (m, 1H), 7.35(t, 1H), 8.08 (s, 1H), 8.12 (d, 1H), 8.21 (d, 1H), 8.45 (s, 1H), 9.51(d, 1H); m/z 612 (M+H)⁺

The following intermediates used in the preparation of Examples 54a-cwere prepared in an analogous fashion.

Structure m/z NMR

618(M + H)⁺ ¹H NMR δ (CDCl₃): 0.00 (s, 3H), 0.03 (s, 3H), 0.84 (s,9H),1.37 (d, 3H), 2.30-2.38 (m, 5H), 3.61-3.79 (m,2H), 4.19 (t, 2H), 4.30(t, 2H), 4.41-4.47 (m, 1H), 6.84-6.86 (m, 1H), 7.62-7.62 (m, 1H),7.72-7.73 (m, 1H),8.10-8.11 (m, 1H), 8.19-8.20 (m, 1H), 9.89 (s, 1H)

598(M + H)⁺ ¹H NMR δ (CDCl₃): 0.00 (s, 3H), 0.03 (s, 3H), 0.83 (s,9H),1.29 (d, 3H), 2.35 (quin, 2H), 3.64-3.79 (m, 2H),2H), 4.19 (t, 2H), 4.32(t, 2H), 4.47-4.51 (m, 1H), 6.96 (s,1H), 7.25 (s, 1H), 7.36 (s, 1H),8.12 (d, 1H), 8.21 (d,1H),8.23 (s, 1H), 8.34 (d, 1H), 8.52 (s, 1H),9.64(s,1H)

597(M + H)⁺ ¹H NMR δ (CDCl₃): 0.00 (s, 3H), 0.03 (s, 3H), 0.84 (s,9H),1.28 (d, 3H), 2.35 (quin, 2H), 3.63-3.78 (m, 2H),4.19 (t, 2H), 4.32 (t,2H), 4.46-4.50 (m, 1H), 6.93 (t,1H), 7.01-7.05 (m, 1H), 7.23-7.23 (m,1H), 7.34 (t,1H), 7.69-7.73 (m, 1H), 8.12 (d, 1H), 8.21 (d, 1H), 8.24(d,1H), 8.31 (d,1H), 8.56 (s, 1H)

The preparation of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoicacid is described below.

3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoicacid

tert-Butyldimethylsilyl chloride (2.78 g, 18.4 mmol) was added to amixture of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoicacid (3.74 g, 9.19 mmol) and 1,8-diazabicyclo(5,4,0)undec-7-ene (2.75mL, 7.36 mmol) in acetonitrile (40 mL) and stirred at RT for 24 hours.The solvent was removed in vacuo and water (80 mL) added to theresultant oil. The mixture was adjusted to pH 10 with 1M sodiumbicarbonate solution and washed with ether to remove any impurities. Theaqueous layer was adjusted to pH 3 with 1M citric acid and extractedinto ethyl acetate (2×100 mL). The combined organics were washed withbrine (50 mL), dried (MgSO₄), filtered and reduced in vacuo to give thedesired compound as a white foam (2.9 g).

¹H NMR δ (CDCl₃): 0.00 (s, 3H), 0.03 (s, 3H), 0.83 (s, 9H), 1.28 (d,3H), 2.35 (quin, 2H), 3.62-3.78 (m, 2H), 4.21 (t, 1H), 4.32 (t, 1H),4.43-4.50 (m, 1H), 6.95-6.98 (m, 1H), 7.42-7.45 (m, 1H), 7.50-7.53 (m,1H), 8.12 (d, 1H), 8.22 (d, 1H); m/z 521 (M+H)⁺

3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoicacid

Lithium hydroxide monohydrate (529 mg, 12.59 mmol) in water (25 mL) wasadded to a solution of methyl3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoate(5.3 g, 12.6 mmol) in THF (50 mL) and stirred at RT for 3 hours. The THFwas removed in vacuo and the aqueous layer was washed with ethyl acetate(50 mL) to remove any impurities. The aqueous layer was acidified andextracted into ethyl acetate (2×50 mL), and the organics washed withbrine, dried (MgSO₄), and concentrated in vacuo to give the desiredcompound as a white foam (3.74 g).

¹H NMR δ (CDCl₃): 1.24 (d, 3H), 2.31 (quin, 2H), 3.65-3.72 (m, 2H), 4.17(t, 2H), 4.29 (t, 2H), 4.47-4.54 (m, 1H), 6.93 (t, 1H), 7.40 (s, 1H),7.46 (s, 1H), 8.08 (d, 1H), 8.19 (d, 1H); m/z 407 (M+H)⁺

Methyl3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoate

A mixture of methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate(2.35 g, 10.39 mmol), 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine(2.41 g, 10.39 mmol) and potassium carbonate (2.87 g, 20.8 mmol) inacetonitrile (20 mL) was stirred in a microwave reactor at 160° C. for 6hours. The solvent was removed in vacuo and the residue partitionedbetween ethyl acetate (50 mL) and water (50 mL). The organic layer waswashed with brine (50 mL), dried (MgSO₄), and the solvent removed invacuo. The crude oil was chromatographed on silica, eluting with 30-100%ethyl acetate in isohexane, to give the desired compound as a yellow oil(5.3 g).

¹H NMR δ (CDCl₃): 1.24 (d, 3H), 1.94 (t, 1H), 2.32 (quin, 2H), 3.65-3.72(m, 2H), 3.83 (s, 3H), 4.16 (t, 2H), 4.28 (t, 2H), 4.47-4.54 (m, 1H),6.90 (t, 1H), 7.37-7.38 (m, 1H), 7.43-7.45 (m, 1H), 8.08 (d, 1H), 8.18(d, 1H); m/z 421 (M+H)⁺

The preparations of methyl3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate and5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine were described earlier.

EXAMPLE 553-{[5-(Azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide

A mixture of3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide(237 mg, 0.77 mmol), 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (151 mg,0.77 mmol) and potassium carbonate (213 mg, 1.54 mmol) in acetonitrile(5 mL) was stirred in a microwave reactor at 140° C. for 5 hours and at160° C. for 10 hours. The mixture was reduced in vacuo and ethyl acetate(50 mL) added. The mixture was washed with water (50 mL), brine (50 mL),dried (MgSO₄), and reduced in vacuo to give a brown oil which waschromatographed on silica, eluting with 0-10% methanol in ethyl acetate,to give the desired compound as a white foam (64 mg).

¹H NMR δ (CDCl₃): 1.29 (d, 3H), 2.38 (quin, 2H), 2.49 (s, 3H), 2.72 (s,1H), 3.75-3.77 (m, 2H), 4.20-4.41 (m, 4H), 4.51-4.59 (m, 1H), 6.95 (t,1H), 6.99 (d, 1H), 7.35 (t, 1H), 7.37-7.38 (m, 1H), 8.05-8.08 (m, 1H),8.40 (d, 1H), 11.08 (s, 1H); m/z 470 (M+H)⁺

The preparation of 5-(azetidin-1-ylcarbonyl)-2-chloropyridine wasdescribed earlier. The preparation of3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamideis described below.

3-Hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,24-thiadiazol-5-yl)benzamide

Iodotrimethylsilane (5.51 mL, 38.7 mmol) was added to3-hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-(3-methyl-1,2,4-thiadiazol-2-yl)benzamide(2.5 g, 7.73 mmol) in acetonitrile (25 mL) and the reaction stirred atRT for 48 hours. Methanol (15 mL) was added and the reaction stirred for1 hour then a saturated solution of sodium thiosulphate (10 mL) wasadded and stirred for 20 mins. The volatiles were removed in vacuo andthe aqueous residue extracted into ethyl acetate (2×150 mL). Theorganics were washed with water, brine, dried (MgSO₄), and reduced invacuo to give a yellow solid. The solid was triturated with DCM and thenwith ethyl acetate to give the desired compound as a white solid (1.44g). ¹H NMR δ (d₆-DMSO): 1.23 (d, 3H), 2.49 (s, 3H), 3.46-3.59 (m, 2H),4.48-4.52 (m, 1H), 4.89 (t, 1H), 6.60 (s, 1H), 7.08 (s, 1H), 7.24 (s,1H), 9.91 (s, 1H), 13.28 (s, 1H); m/z 310 (M+H)⁺

The preparation of3-hydroxy-5-{[(1S)-2-methoxy-(1-methylethyl)oxy}-N-(3-methyl-1,2,4-thiadiazol-2-yl)benzamidewas described earlier.

EXAMPLE 56N-(1-methyl-1H-pyrazol-3-yl)-3-{[6-(pyrrolidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Copper (I) iodide (95 mg, 0.5 mmol),2,2,6,6-tetramethyl-3,5-heptanedione (0.42 mL, 2.0 mmol) and cesiumcarbonate (489 mg, 1.5 mmol) were added to a solution of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide(152 mg, 0.5 mmol) and 5-bromo-2-(pyrrolidin-1-ylcarbonyl)pyridine (141mg, 0.55 mmol) in NMP (5 mL) and the stirred mixture heated at 160° C.in a microwave reactor for 12 hours. The mixture was cooled to RT andpressure, the mixture partitioned between water (75 mL) and ethylacetate (50 mL), the organic layer washed with brine, dried (MgSO₄) andevaporated to a residue which was chromatographed on silica, elutingwith ethyl acetate, to give the desired material (81 mg).

¹H NMR δ (CDCl₃): 1.8-1.95 (m, 4H), 2.0-2.2 (m, 2H), 3.6 (m, 2H), 3.75(s, 3H), 3.85 (m, 2H), 3.95 (m, 2H), 4.9 (m, 1H), 6.65 (m, 1H), 6.75 (m,1H), 7.1 (m, 1H), 7.2 (s, 1H), 7.25 (m, 1H), 7.3 (dd, 1H), 7.8 (d, 1H),8.25 (d, 1H), 8.8 (s, 1H); m/z 478 (M+H)⁺.

The preparation of3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamidewas described earlier.

The preparation of 5-bromo-2-(pyrrolidin-1-ylcarbonyl)pyridine isdescribed below.

5-Bromo-2-(pyrrolidin-1-ylcarbonyl)pyridine

Oxalyl chloride (0.83 mL; 9.3 mmol) and DMF (1 drop) were added to asolution of 5-bromoisonicotinic acid (1.57 g; 7.75 mmol) and 4M hydrogenchloride in dioxan (1.93 mL; 7.75 mmol) in DCM (50 mL). The mixture wasstirred at RT for 18 hours, the DCM removed in vacuo and the residueazeotroped with toluene (2×15 mL). The residue was and added to asolution of pyrrolidine (0.78 mL; 9.3 mmol) and triethylamine (2.6 mL;18.6 mmol) in DCM (40 mL) and the mixture stirred at RT for 6 hours. TheDCM was removed in vacuo, the residue partitioned between water (75 mL)and ethyl acetate (100 mL), the organic layer washed with brine, dried(MgSO₄) and evaporated to a residue which was chromatographed on silica,eluting with 50% ethyl acetate in iso hexane, to give the desiredmaterial (1.40 g). ¹H NMR δ (CDCl₃): 1.85 (m, 4H), 3.6 (m, 2H), 3.7 (s,3H), 7.7 (d, 1H), 7.85 (s, 1H), 8.55 (s, 1H); m/z 257 (M+H)⁺.

EXAMPLE 573-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-pyrazin-2-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.095 mL, 0.75 mmol) was addedto a solution of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid (250 mg, 0.65 mmol) in DCM (6 mL) and stirred at RT for 30-40minutes. 2-Aminopyrazine (125 mg, 1.31 mmol) and pyridine (0.106 mL,1.31 mmol) were added and the reaction stirred at RT for 2 hours. Thesolvent was removed in vacuo, water (20 mL) was added and the mixturewas extracted with ethyl acetate (3×20 mL). The organic extracts werecombined and washed with 2N hydrochloric acid (20 mL), a saturatedsolution of sodium bicarbonate (20 mL), water (20 mL), brine (20 mL),dried (MgSO₄) and evaporated in vacuo. The crude product waschromatographed on silica, eluting with a gradient of 0-10% methanol inDCM, to give the desired compound (71 mg).

¹H NMR δ (CDCl₃): 2.13-2.30 (m, 2H), 2.32-2.39 (m, 2H), 3.89-4.04 (m,4H), 4.25 (t, 2H), 4.71 (t, 2H), 4.97-5.01 (m, 1H), 6.77 (t, 1H), 7.16(t, 1H), 7.25 (s, 1H), 7.40 (dd, 1H), 8.14 (d, 1H), 8.28 (dd, 1H), 8.34(d, 1H), 8.38 (s, 1H), 8.40 (d, 1H), 9.66 (d, 1H); m/z 462 (M+H)⁺, 460(M−H)⁻

The following compounds were prepared in an analogous fashion from3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid and either 1,1-dimethylethyl3-amino-5-methyl-1H-pyrazole-1-carboxylate or 1,1-dimethylethyl3-amino-1H-pyrazole-1-carboxylate. The material produced was dissolvedin acetonitrile (3 mL) and heated at 150° C. in a microwave reactor for10 minutes to give the desired material after chromatography.

Example Structure m/z NMR 57a

464(M + H)⁺462(M − H)⁻ ¹H NMR δ (CDCl₃): 2.12-2.27 (2H, m),2.31-2.39,(2H, m), 2.33 (3H, s), 3.87-4.01(4H, m), 4.24 (2H, t), 4.70 (2H, t),4.95-4.98(1H, m), 6.57 (1H, s), 6.73 (1H, t), 7.13 (1H,t), 7.24 (1H, t),7.35-7.38 (1H, m), 8.10 (1H,d), 8.31 (1H, d), 8.79 (1H, s) 57b

450(M + H)⁺448(M − H)⁻ ¹H NMR δ (CDCl₃): 2.11-2.27 (2H, m),2.30-2.38(2H, m), 3.87-4.02 (4H, m), 4.22(2H, t), 4.69 (2H, t), 4.95-4.97 (1H,m), 6.74(1H, t), 6.77 (1H, s), 7.19 (1H, s), 7.30 (1H,s), 7.32-7.35 (1H,m), 7.51 (1H, d), 8.06(1H, d), 8.30 (1H, d), 9.59 (1H, s)

The preparations of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate weredescribed earlier.

The preparation of 1,1-dimethylethyl3-amino-5-methyl-1H-pyrazole-1-carboxylate is described below.

1,1-Dimethylethyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate

5-Methyl-1H-pyrazol-3-amine (800 mg, 8.25 mmol) was dissolved in DMF (10mL) at 0° C. and treated with sodium hydride (336 mg, 8.25 mmol)followed by stirring for a further 30 minutes. Warmed di-tert-butyldicarbonate (1.80 g, 8.25 mmol) was then slowly added via syringe over 5min and the reaction was allowed to warm to RT and stirred for a further1 hour. The reaction was taken up in saturated aqueous sodiumhydrogencarbonate (50 mL) and ethyl acetate (100 mL). The organic layerwas separated then dried (MgSO₄), filtered and evaporated. Purificationby column chromatography, eluting with 50-100% ethyl acetate inisohexane, afforded the title compound as a colourless oil (380 mg).

¹H NMR δ (CDCl₃): 1.62 (s, 9H), 2.43 (s, 3H), 3.87 (br. s, 2H), 5.60 (s,1H)

EXAMPLE 583-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

1-Chloro-N,N-2-trimethylpropenylamine (0.08 mL, 0.60 mmol) was added toa solution of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoicacid (215 mg, 0.5 mmol) in DCM (5 mL) and the reaction stirred at RT for30-40 minutes. Pyridine (0.08 mL, 1.0 mmol) and 2-amino-5-methylpyrazine(108 mg, 1.0 mmol) were added and the reaction stirred for 16 hoursbefore being concentrated in vacuo and water (20 mL) added. The mixturewas extracted with ethyl acetate (3×20 mL), washed with 1N hydrochloricacid (20 mL), a saturated solution of sodium hydrogen carbonate (20 mL),brine (20 mL), dried (MgSO₄) and concentrated in vacuo. The crudeproduct was chromatographed on silica, eluting with a gradient of 0-10%methanol in DCM, to give the desired compound as a white solid (150 mg).¹H NMR δ (CDCl₃): 2.40 (quintet, 2H), 2.56 (s, 3H), 4.22-4.31 (m, 2H),4.32-4.40 (m, 2H), 4.62-4.82 (m, 5H), 7.06 (t, 1H), 7.38 (t, 1H), 7.47(t, 1H), 8.15 (s, 1H), 8.17 (s, 1H), 8.25 (d, 1H), 8.46 (s, 1H), 9.55(s, 1H); m/z 518 (M+H)⁺, 516 (M−H)⁻

The following compounds were prepared in an analogous fashion from theappropriate benzoic acid and either 2-amino-5-methylpyrazine,1,1-dimethylethyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate or1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate. In the instanceswhere either 1,1-dimethylethyl3-amino-5-methyl-1H-pyrazole-1-carboxylate or 1,1-dimethylethyl3-amino-1H-pyrazole-1-carboxylate were used, an additional step wasrequired to obtain the desired material. This additional step requiredthe material to be dissolved in acetonitrile (3 mL) and heated at 150°C. in a microwave reactor for 10 minutes, the desired material was thenisolated after chromatography.

Example Structure m/z NMR 58a

492(M + H)⁺490(M − H)⁻ ¹H NMR δ (CDCl₃): 2.39 (quin, 2H), 4.22 (t,2H),4.33 (t, 2H), 4.59-4.81 (m, 5H), 6.86(s, 1H), 6.99 (s, 1H), 7.37 (s,1H), 7.41 (s,2H), 8.16 (d, 1H), 8.19 (d, 1H), 10.32 (s, 1H) 58b

506(M + H)⁺504(M − H)⁻ ¹H NMR δ (CDCl₃): 2.24 (s, 3H), 2.38 (quin,2H),4.23 (t, 2H), 4.34 (t, 2H), 4.59-4.79 (m,5H), 6.59 (s, 1H), 7.00 (t,1H), 7.34 (s, 1H),7.37 (s, 1H), 8.16 (d, 1H), 8.19 (d, 1H), 9.95(s, 1H)58c

459(M + H)⁺457(M − H)⁻ ¹H NMR δ (d₆-DMSO): 2.25-2.35 (m, 2H),4.12-4.18(m, 2H), 4.50-4.70 (m, 7H), 6.65(s, 1H), 6.9 (s, 1H), 7.35 (s, 1H), 7.37(s,1H), 7.45 (s, 1H), 8.25 (s, 1H), 8.70 (s, 1H),10.60 (s, 1H) 58d

485(M + H)⁺483(M − H)⁻ ¹H NMR δ (CDCl₃): 2.34-2.42 (m, 2H),2.58 (s, 3H),4.26 (t, 2H), 4.69 (t, 2H), 4.63-4.81 (m, 5H), 7.05 (t, 1H), 7.37 (t,1H), 7.45-7.46 (m, 1H), 8.14 (d, 1H), 8.34 (s, 1H), 8.37(d, 1H), 8.86(d, 1H), 9.53 (d, 1H)

The preparations of 1,1-dimethylethyl3-amino-5-methyl-1H-pyrazole-1-carboxylate or 1,1-dimethylethyl3-amino-1H-pyrazole-1-carboxylate were described earlier. Thepreparation of3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoicacid is described below.

3-{[5-(Azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoicacid

A mixture of methyl3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoate(3.6 g, 8.2 mmol) in THF (50 mL) and water (50 mL) was treated with 1Msodium hydroxide solution (8.2 mL, 8.2 mmol) and allowed to stir at RTfor 210 minutes. The THF was removed in vacuo, the residue filtered andextracted with ethyl acetate (30 mL). The aqueous layer was acidifiedwith 2N hydrochloric acid, extracted with ethyl acetate (3×50 mL) andthe combined organic extracts washed with water (10 mL), brine (10 mL)and concentrated in vacuo to give the desired material as a pale yellowfoam (2.84 g). ¹H NMR δ (CDCl₃): 2.36-2.44 (m, 2H), 4.26 (t, 2H), 4.37(t, 2H), 4.62-4.79 (m, 5H), 7.08 (t, 1H), 7.56-7.57 (m, 1H), 7.58-7.59(m, 1H), 8.17 (d, 1H), 8.27 (d, 1H); m/z 426 (M+H)⁺, 424 (M−H)⁻

3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoicacid was prepared in an analogous fashion from methyl3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoate

Structure m/z NMR

394(M + H)⁺,392(M − H)⁻ ¹H NMR δ (d₆-DMSO): 2.26-2.34 (m, 2H),4.08-4.15(m, 2H), 4.56 (t, 2H), 4.60-5.10 (m,5H), 7.29 (t, 1H), 7.38-7.39 (m,1H), 7.46-7.47 (m, 1H), 8.56 (d, 1H), 8.65-8.67 (m, 1H)

The preparation of methyl3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoateis described below.

Methyl3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoate

A solution of methyl3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxybenzoate (1.78 g, 7.24mmol), potassium carbonate (2.0 g, 14.5 mmol) and5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (2.08 g, 8.7 mmol) inacetonitrile (15 mL) was heated in a microwave reactor at 130° C. for 1hour. The solution was diluted with ethyl acetate (150 mL), washed withwater (3×50 mL), brine (20 mL), dried (MgSO₄), and the solvent removedin vacuo to give the desired material as an orange oil (3.6 g). ¹H NMR δ(CDCl₃): 2.35-2.44 (m, 2H), 3.91 (s, 3H), 4.24-4.27 (m, 2H), 4.34-4.37(m, 2H), 4.62-4.81 (m, 5H), 7.04 (t, 1H), 7.51 (t, 1H), 7.55 (m, 1H),8.15 (d, 1H), 8.25 (d, 1H); m/z 441 (M+H)⁺

Methyl3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoatewas prepared in an analogous fashion from methyl3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxybenzoate.

Structure m/z NMR

408(M + H)⁺ ¹H NMR δ (CDCl₃): 2.34-2.43 (m, 2H), 3.91 (s,3H), 4.26 (t,2H), 4.59-4.79 (m, 5H), 4.65-4.71(m, 2H), 7.03 (t, 1H), 7.49-7.50 (m,1H), 7.54-7.55 (m, 1H), 8.33 (d, 1H), 8.84-8.86 (m, 1H)

The preparation of methyl3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxybenzoate is describedbelow.

Methyl 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxybenzoate

10% Palladium on charcoal (Pd/C; 50 mg) was added to a mixture of methyl3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoate(1.2 g, 3.62 mmol) and ammonium formate (500 mg, 8.0 mmol) in ethanol (7mL) and then heated at 140° C. for 20 minutes in a microwave reactor.The reaction was repeated on the same scale and the two reactionmixtures combined, filtered and filtrate concentrated in vacuo to givethe desired material as a pale yellow oil (2.1 g). ¹H NMR δ (CDCl₃):3.82 (s, 3H), 4.58-4.77 (m, 5H), 6.72 (t, 1H), 7.17-7.22 (m, 2H); m/z245 (M−H)⁻

The preparation of methyl3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoatewas described earlier.

EXAMPLE 593-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

1M Hydrochloric acid (5 mL) was added to a solution of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide(90 mg, 0.16 mmol) in methanol (5 mL) and the mixture stirred at RT for1 hour. The methanol was removed in vacuo, the residue adjusted to pH6and then extracted into ethyl acetate (3×50 mL). The combined organicswere washed with brine (50 mL), dried (MgSO₄), and reduced in vacuo togive a yellow oil which was chromatographed on silica, eluting with 0-5%methanol in ethyl acetate, to give the desired compound as a white foam(28 mg).

¹H NMR δ (CDCl₃): 1.33 (d, 3H), 2.11 (s, 1H), 2.38 (quin, 2H), 2.55 (s,3H), 3.74-3.82 (m, 2H), 4.26 (t, 2H), 4.55-4.62 (m, 1H), 4.69 (t, 2H),6.97 (t, 1H), 7.30 (t, 1H), 7.40 (t, 1H), 8.13 (s, 1H), 8.35 (d, 1H),8.41 (s, 1H), 8.85 (d, 1H), 9.53 (d, 1H); m/z 465 (M+H)⁺

The preparation of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamideis described below.

3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-ylbenzamide

A mixture of3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide(0.12 g, 0.29 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (57 mg,0.29 mmol) and potassium carbonate (80 mg, 0.57 mmol) in acetonitrile (5mL) was stirred in a microwave reactor at 140° C. for 1 hour. Themixture was reduced in vacuo and ethyl acetate (50 mL) added. Themixture was washed with water (50 mL), brine (50 mL), dried (MgSO₄),filtered and reduced in vacuo to give a brown oil which waschromatographed on silica, eluting with 50 to 100% ethyl acetate inisohexane, to give the desired compound as a colourless oil (90 mg). ¹HNMR δ (CDCl₃): −0.03 (s, 3H), 0.00 (s, 3H), 0.81 (s, 9H), 1.26 (d, 3H),2.32 (quin, 2H), 2.49 (s, 3H), 3.61-3.76 (m, 2H), 4.20 (t, 2H), 4.46(sextet, 1H), 4.62 (t, 2H), 6.91 (t, 1H), 7.21 (t, 1H), 7.32 (t, 1H),8.07 (s, 1H), 8.28 (d, 1H), 8.30 (s, 1H), 8.79 (d, 1H), 9.48 (d, 1H).m/z 579 (M+H)⁺

3-[((1S)-2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide

Lithium hydroxide monohydrate (0.38 g, 9.12 mol) in water (20 mL) wasadded to a solution of3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide(1.94 g, 3.65 mol) in THF (40 mL) and stirred at RT for 20 hours. TheTHF was removed in vacuo and the aqueous layer was adjusted to pH7.Ethyl acetate (50 mL) and water (50 mL) were added then the aqueouslayer re-extracted into ethyl acetate (50 mL) and the combined organicswashed with water (50 mL), brine (50 mL), dried (MgSO₄), filtered andreduced in vacuo. The crude material was chromatographed on silica,eluting with 20-50% ethyl acetate in isohexane, to give the desiredmaterial as a white solid (0.8 g). ¹H NMR δ (CDCl₃): 0.04 (s, 3H), 0.08(s, 3H), 0.87 (s, 9H), 1.30 (d, 3H), 2.56 (s, 3H), 3.65-3.81 (m, 2H),4.46-4.51 (m, 1H), 5.63 (s, 1H), 6.63 (t, 1H), 6.98 (t, 1H), 7.04 (t,1H), 8.15 (s, 1H), 8.41 (s, 1H), 9.57 (s, 1H); m/z 418 (M+H)⁺

3-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-ylbenzamide

tert-Butyldimethylsilyl chloride (2.61 g, 17.31 mmol) was added to asolution of3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide(1.5 g, 4.95 mmol) and imidazole (2.36 g, 34.62 mmol) in DMF (15 mL) andthe reaction stirred at RT for 24 hours. Water was added and the productextracted into ether (2×100 mL). The combined organics were washed withbrine, dried (MgSO₄), filtered and reduced in vacuo to give a yellow oilwhich was chromatographed on silica, eluting with 0-40% ethyl acetate inisohexane, to give the desired material as a colourless oil (1.94 g).

¹H NMR δ (CDCl₃): −0.03 (s, 3H), 0.01 (s, 3H), 0.16 (s, 6H), 0.81 (s,9H), 0.92 (s, 9H), 1.23 (d, 3H), 2.48 (s, 3H), 3.58-3.74 (m, 2H),4.37-4.42 (m, 1H), 6.54 (t, 1H), 6.86 (t, 1H), 6.99 (t, 1H), 8.06 (s,1H), 8.21 (s, 1H), 9.48 (d, 1H).

3-Hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

Trimethylsilyl iodide (6.06 mL, 42.75 mmol) was added to a solution of3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide(2.71 g, 8.55 mmol) in dry acetonitrile (150 mL) and stirred for 24hours. Methanol (30 mL) was added to quench the reaction and stirred for10 minutes. 10% w/v Aqueous sodium thiosulfate pentahydrate (20 mL) wasadded to the mixture and the organic solvents removed in vacuo. Theresidue was brought to pH5 with 1M hydrochloric acid and ethyl acetate(80 mL) added. A yellow solid (1.4 g) was separated by filtration. Theaqueous filtrate was reextracted into ethyl acetate (2×80 mL) and thecombined organic layers dried (MgSO₄), filtered and the solvents removedin vacuo. This residue was combined with the yellow solid obtained aboveand purified by column chromatography, eluting with 5% to 10% methanolin DCM, to give the title compound (1.70 g)

¹H NMR δ (d₆-DMSO): 1.21 (d, 3H), 2.50 (s, 3H), 3.40-3.60 (m, 2H), 4.45(sex, 1H), 4.80 (t, 1H), 6.50 (s, 1H), 6.97 (s, 1H), 7.08 (s, 1H), 8.32(s, 1H), 9.21 (s, 2H), 9.63 (s, 1H), 10.80 (brs, 1H). m/z 304 (M+H)⁺

The preparation of3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamidewas described earlier.

Example 59,3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamidewas also prepared in the following manner.

A mixture of3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide(3.03 g, 10.0 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (2.17 g,11.0 mmol) and potassium carbonate (4.14 g, 30.0 mmol) in acetonitrile(30.3 mL) was heated at 60° C. overnight. The solvent was removed byevaporation and the residue partitioned between ethyl acetate (15 vol)and water (10 vol). The aqueous phase was further extracted into ethylacetate and the combined organics washed water, brine, dried (MgSO₄),filtered and the solvent removed in vacuo. The residue waschromatographed on silica, eluting with 0.5-6% methanol in ethylacetate, to give the desired material as a foam (3.1 g). A sample ofthis material (100 mg) was dissolved in the minimum volume ofacetonitrile then isohexane (5 mL) added. The mixture was stirred for 3days, the liquid decanted and the residue triturated with diethyl ether.The crystalline material was collected by filtration. ¹H NMR δ(d₆-DMSO): 1.25 (d, 3H), 2.30 (quin, 2H), 2.48 (s, 3H), 3.49-3.61 (m,2H), 4.09 (t, 2H), 4.55-4.63 (m, 3H), 4.92 (t, 1H), 7.12 (t, 1H), 7.47(t, 1H), 7.57 (t, 1H), 8.37 (d, 1H), 8.58 (d, 1H), 8.69 (d, 1H), 9.26(d, 1H), 11.06 (s, 1H); m/z 465 (M+H)⁺. Mpt (melting onset) 100.6° C.

The title compound was also crystallised by stirring a slurry of thecompound in ethyl acetate (melting point 125.0° C.), toluene,nitromethane or methanol.

EXAMPLE 603-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-1H-pyrazol-3-ylbenzamide

Trifluoroacetic acid (2 mL) was added to a solution of 1,1-dimethylethyl3-({[3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)phenyl]carbonyl}amino)-1H-pyrazole-1-carboxylate(115 mg, 0.17 mmol) in DCM (16 mL) and stirred at RT for 2 hours. Thesolvent was removed in vacuo, DCM (20 mL) added and the mixture washedwith water (20 mL), a saturated solution of sodium bicarbonate (20 mL),brine (20 mL), dried (MgSO₄), filtered and reduced in vacuo to give thedesired compound as a white foam (93 mg).

¹H NMR δ (CDCl₃): 1.36 (d, 3H), 2.37 (quin, 2H), 3.93-4.02 (m, 2H), 4.24(t, 2H), 4.59-4.69 (m, 3H), 6.24 (t, 1H), 6.82 (s, 1H), 6.89 (t, 1H),7.29-7.31 (m, 1H), 7.36-7.38 (m, 1H), 7.40 (d, 1H), 8.35 (d, 1H), 8.79(d, 1H), 10.23 (s, 1H), 10.48 (s, 1H); m/z 489 (M+H)⁺

The preparation of 1,1-dimethylethyl3-({[3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)phenyl]carbonyl}amino)-1H-pyrazole-1-carboxylateis described below.

1,1-Dimethylethyl3-({[3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)phenyl]carbonyl}amino)-1H-pyrazole-1-carboxylate

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.12 mL, 0.92 mmol) was addedto a solution of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoicacid (0.26 g, 0.61 mmol) in DCM (8 mL) and stirred for 1 hour.1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (169 mg, 0.92 mmol)then pyridine (0.1 mL, 1.23 mmol) were added and stirred for a further20 hours. The reaction mixture was reduced in vacuo and ethyl acetate(50 mL) and water (50 mL) were added. The aqueous layer was re-extractedinto ethyl acetate (50 mL) and the combined organics washed with water(50 mL), brine (50 mL), dried (MgSO₄), filtered and reduced in vacuo.The crude oil was chromatographed on silica, eluting with 25-50% ethylacetate in isohexane, to give the desired compound as a colourless oil(100 mg).

¹H NMR δ (CDCl₃): 1.38 (d, 3H), 1.62 (s, 9H), 2.38 (quin, 2H), 3.93-4.04(m, 2H), 4.26 (t, 2H), 4.61-4.65 (m, 1H), 4.69 (t, 2H), 6.26 (t, 1H),6.95 (t, 1H), 7.08 (d, 1H), 7.25-7.26 (m, 1H), 7.33 (t, 1H), 8.01 (d,1H), 8.34 (d, 1H), 8.84 (s, 1H), 8.85 (d, 1H); m/z 587 (M−H)⁻

The preparation of 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylatewas described earlier.

The preparation of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoicacid is described below.

3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoicacid

Lithium hydroxide monohydrate (48 mg, 1.13 mmol) in water (5 mL) wasadded to a solution of methyl3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoate(0.33 g, 0.75 mmol) in THF (10 mL) and stirred at RT for 20 hours. TheTHF was removed in vacuo and the aqueous layer washed with ethyl acetate(50 mL) to remove any impurities. The aqueous layer was acidified andextracted into ethyl acetate (2×50 mL), washed with brine, dried(MgSO₄), filtered and the solvent removed in vacuo to give the desiredcompound as a white foam (0.26 g). m/z 424 (M+H)⁺

Methyl3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)benzoate

A mixture of methyl3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxybenzoate(0.28 g, 1.01 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (201 mg,1.01 mmol) and potassium carbonate (280 mg, 2.03 mmol) in acetonitrile(5 mL) was stirred in a microwave reactor at 140° C. for 5 hours. Thereaction mixture was reduced in vacuo, ethyl acetate (50 mL) added andthe organics washed with water (50 mL), brine (50 mL), dried (MgSO₄),filtered and reduced in vacuo. The crude oil was chromatographed onsilica, eluting with 20 to 70% ethyl acetate in isohexane, to give thedesired compound as a colourless oil (330 mg). ¹H NMR δ (CDCl₃): 1.38(d, 3H), 2.37 (quin, 2H), 3.90 (s, 3H), 3.93-4.04 (m, 2H), 4.26 (d, 2H),4.61-4.70 (m, 3H), 6.25 (t, 1H), 6.95 (t, 1H), 7.43-7.44 (m, 1H),7.49-7.50 (m, 1H), 8.32 (d, 1H), 8.85 (d, 1H); m/z 438 (M+H)⁺

Methyl3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxybenzoate

Methyl3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-[(phenylmethyl)oxy]benzoate(0.48 g, 1.08 mmol) was dissolved in ethanol (10 mL) and THF (10 mL) andthe flask evacuated and purged with argon (3 times). 10% Palladium oncarbon (140 mg) was added and the flask further evacuated and finallypurged with hydrogen gas. The reaction mixture was stirred at RT for 20hours until completion. The reaction mixture was evacuated and purgedwith argon (3 times) then the catalyst removed by filtration throughCelite®. The filtrate was concentrated in vacuo to give the desiredcompound as a colourless oil (1.05 g). ¹H NMR δ (CDCl₃): 1.35 (d, 3H),3.90 (s, 3H), 3.90-4.02 (m, 2H), 4.57-4.64 (m, 1H), 5.20 (s, 1H), 6.26(t, 1H), 6.63 (t, 1H), 7.14-7.15 (m, 1H), 7.17-7.18 (m, 1H); m/z 275(M−H)⁻

The preparations of methyl3-({(1S)-2-[(difluoromethyl)oxy]1-methylethyl}oxy)-5-[(phenylmethyl)oxy]benzoateand 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine were described earlier.

EXAMPLE 613-{[5-(Azetidin-1-ylsulfonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

Cesium carbonate (293 mg, 0.9 mmol) was added to a solution of3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide(95 mg, 0.3 mmol) and5-(azetidin-1-ylsulfonyl)-2-chloro-4-methyl-1,3-thiazole (90 mg, 0.36mmol) in acetonitrile (5 mL) and the stirred mixture heated in amicrowave reactor at 120° C. for 1 hour. The mixture was cooled to RTand pressure, the acetonitrile removed in vacuo, and the residuepartitioned between water (15 mL) and ethyl acetate (30 mL). The organiclayer was washed with brine, dried (MgSO₄) and evaporated in vacuo to aresidue which was chromatographed on silica, eluting with 60% ethylacetate in isohexane, to give the desired material as a colourless solid(79 mg).

¹H NMR δ (CDCl₃): 1.3 (d, 3H), 2.15 (m, 2H), 2.5 (s, 3H), 2.5 (s, 3H),3.35 (s, 3H), 3.45-3.55 (m, 2H), 3.85 (t, 4H), 4.55 (m, 1H), 7.0 (d,1H), 7.35 (d, 2H), 8.05 (s, 1H), 8.3 (s, 1H), 9.45 (s, 1H); m/z 534(M+H)⁺

The preparation of3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamidewas described earlier.

The preparation of5-(azetidin-1-ylsulfonyl)-2-chloro-4-methyl-1,3-thiazole is describedbelow.

5-(Azetidin-1-ylsulfonyl)-2-chloro-4-methyl-1,3-thiazole

A solution of 2-chloro-4-methylthiazole-5-sulphonylchloride (462 mg; 2.0mmol) in DCM (5 mL) was added to an ice-cold solution of azetidinehydrochloride (196 mg; 2.1 mmol) and triethylamine (1.0 mL; 7.2 mmol) inDCM (15 mL) and the mixture stirred at 0° C. for 30 minutes. The DCM wasremoved in vacuo to give a residue which was partitioned between water(50 mL) and ethyl acetate (75 mL). The organic layer was washed withbrine, dried (MgSO₄) and evaporated to a residue which waschromatographed on silica, eluting with 10% ethyl acetate in isohexane,to give the desired material as a solid which was crystallised fromethyl acetate and isohexane (100 mg).

¹H NMR δ (CDCl₃): 2.2 (dt, 2H), 2.65 (s, 3H), 3.9 (t, 4H); m/z 253(M+H)⁺

EXAMPLE 623-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.088 mL, 0.66 mmol) was addedto a solution of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid (171 mg, 0.44 mmol) in DCM (10 mL) and the reaction was stirred atRT for 30 minutes. After this time 1-(difluoromethyl)pyrazol-3-aminehydrochloride (75 mg, 0.44 mmol) and DIPEA (0.154 mL, 0.89 mmol) wereadded sequentially. The resulting solution was stirred at RT for 16hours after which time the solvent was removed in vacuo and ethylacetate (20 mL) and water (20 mL) were added. The aqueous phase wasextracted with ethyl acetate (2×20 mL), washed with a saturated solutionof sodium hydrogen carbonate (20 mL), and brine (20 mL). The combinedorganic extracts were dried (MgSO₄), filtered and evaporated. Theresidue was purified by flash column chromatography on silica, elutingwith 50-100% ethyl acetate in isohexane, to give the desired product asa white solid (132 mg). ¹H NMR δ (CDCl₃): 2.40-2.12 (m, 4H), 4.03-3.89(m, 4H), 4.25 (t, 2H), 4.71 (t, 2H), 5.01-4.96 (m, 1H), 6.76 (t, 1H),7.03 (t, 1H), 7.08 (d, 1H), 7.11 (s, 1H), 7.22 (s, 1H), 7.38 (dd, 1H),7.75 (d, 1H), 8.13 (d, 1H), 8.33 (d, 1H), 8.50 (s, 1H); ¹⁹F NMR δ(CDCl₃): −93.84; m/z 500 (M+H)⁺.

The following compounds were made in an analogous fashion.

Example Structure m/z NMR 62a

503(M + H)⁺ ¹H NMR δ (CDCl₃): 1.34 (d, 4H), 2.37 (quin,2H), 3.40 (s,3H), 3.51 (dd, 2H), 3.59 (dd, 2H),4.25 (t, 2H), 4.60 (m, 1H), 4.68 (t,2H), 6.96 (t,1H), 7.02 (s, 1H), 7.02 (t, 1H), 7.08 (d, 1H),7.26 (s, 1H),7.37 (t, 1H), 7.73 (d, 1H), 8.33 (d,1H), 8.54 (s, 1H), 8.85 (d, 1H) 62b

502(M + H)⁺ ¹H NMR δ (CDCl₃): 1.26 (d, 3H), 2.24-2.32(m, 2H), 3.46-3.55(m, 2H), 4.08 (t, 2H), 4.59(t, 2H), 4.77 (m, 1H), 6.89 (d, 1H), 6.97(t,1H), 7.30 (s, 1H), 7.50 (s, 1H), 7.58 (dd, 1H),7.71 (t, 1H), 8.00 (d,1H), 8.15 (d, 1H), 8.42(d, 1H), 11.22 (s, 1H)

The preparations of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoicacid,3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid and3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid were described earlier.

The preparation of 1-(difluoromethyl)pyrazol-3-amine is described in theliterature [WO2005090332, PCT Int. Appl. (2005)].

EXAMPLE 633-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

1-Chloro-N,N,2-trimethyl-1-propenylamine (0.042 mL, 0.31 mmol) was addedto a solution of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid (0.102 g, 0.0.31 mmol) in DCM (3 mL) under argon and stirred at RTfor 40 minutes. 2-Amino-5-methylpyrazine (57 mg, 0.52 mmol) and pyridine(0.043 mL, 0.52 mmol) were added and the reaction stirred for a further3 hours. The solvent was removed in vacuo and the residue taken up inethyl acetate (30 mL), washed with water (2×10 mL), a saturated aqueoussolution of sodium bicarbonate (10 mL), brine (10 mL), dried (MgSO₄),filtered, and evaporated in vacuo. The crude material waschromatographed on silica, eluting with a gradient of 60-100% ethylacetate in isohexane, to give the desired compound as a white foam (86mg).

¹H NMR δ (CDCl₃): 1.35 (d, 3H), 2.32-2.44 (m, 2H), 2.56 (s, 3H), 3.41(s, 3H), 3.47-3.64 (m, 2H), 4.26 (t, 2H), 4.62 (q, 1H), 4.69 (t, 2H),6.98 (s, 1H), 7.29 (s, 1H), 7.41 (s, 1H), 8.13 (s, 1H), 8.35 (s, 2H),8.86 (s, 1H), 9.54 (s, 1H); m/z 479 (M+H)⁺

The preparation of3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid is described below.

3-{[5-(Azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoicacid

Methyl3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate(1.06 g, 2.6 mmol) was dissolved in THF (24 mL) and methanol (8 mL) then1N lithium hydroxide solution (3.12 mL) added, followed by the dropwiseaddition of water (10 mL). The resultant solution was stirred for 3hours at RT, a further portion of 1N lithium hydroxide solution (1.3mL), the reaction stirred a further 2 hours, then further 1N lithiumhydroxide solution (0.6 mL) added and stirring continued for anotherhour. The organics were removed by evaporation under reduced pressure,the aqueous solution was washed with diethyl ether (10 mL) thenacidified with 2N hydrochloric acid and extracted with ethyl acetate(3×20 mL). The combined organics were washed with water (10 mL), brine(10 mL) and evaporated to dryness under reduced pressure to give thedesired compound as a white solid (887 mg).

¹H NMR δ (CDCl₃): 1.34 (d, 3H), 2.38 (quin, 2H), 3.41 (s, 3H), 3.47-3.64(m, 2H), 4.27 (t, 2H), 4.55-4.65 (m, 1H), 4.69 (t, 2H), 6.99 (s, 1H),7.45 (s, 1H), 7.55 (s, 1H), 8.33 (s, 1H), 8.84 (s, 1H); m/z 388 (M+H)⁺

Methyl3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate

A mixture of methyl3-hydroxy-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate (727 mg, 3mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (712 mg, 3.6 mmol) andpotassium carbonate (828 mg, 6 mmol) in DMA (10 mL) was stirred at 120°C. for 2 hours. The solution was diluted with ethyl acetate (150 mL)washed with water (3×50 mL), brine (20 mL), dried (MgSO₄), filtered andthe solvent removed in vacuo. The residue was purified by chromatographyon silica, eluting with 50% ethyl acetate in isohexane, to give thedesired material as a colourless oil (1.07 g). ¹H NMR δ (CDCl₃): 1.27(d, 3H), 2.4 (quintet, 2H), 3.4 (s, 3H), 3.5-3.6 (m, 2H), 3.9 (s, 3H),4.25 (t, 2H), 4.53 (q, 1H), 4.7 (t, 2H), 6.95 (s, 1H), 7.4 (s, 1H), 7.5(s, 1H), 8.3 (s, 1H), 8.85 (s, 1H); m/z 402 (M+H)⁺

The preparation of 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine wasdescribed earlier.

Methyl 3-hydroxy-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoate

A solution of methyl3-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoatein THF (5 mL) and ethanol (5 mL), containing 10% palladium on carbon,was stirred under an atmosphere of hydrogen for 16 hours. The palladiumon carbon was removed by filtration and the filtrate evaporated underreduced pressure to give the desired material as a clear gum (723 mg).

¹H NMR δ (CDCl₃): 1.31 (d, 3H), 3.42 (s, 3H), 3.48-3.64 (m, 2H), 3.88(s, 3H), 4.54-4.63 (m, 1H), 5.75 (s, 1H), 6.64 (s, 1H), 7.11 (s, 1H),7.17 (s, 1H); m/z 241 (M+H)⁺

Methyl3-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoate

DIAD (4.6 g, 0.029 mol) was added dropwise to a solution of methyl3-hydroxy-5-{[phenylmethyl]oxy}benzoate (6 g, 0.023 mol),(S)-(+)-1-methoxy-2-propanol (2.59 g, 0.029 mol) and triphenylphosphine(7.53 g, 0.029 mol) in THF (100 mL), under argon, at 0° C. The reactionwas stirred at 0° C. for 1 hour and at RT for 20 hours. The volatileswere removed in vacuo and isohexane/ethyl acetate 2:1 added followed bystirring for 1 hour. A white solid was removed by filtration and thefiltrate was evaporated to a residue which was chromatographed onsilica, eluting with a gradient of 0-20% ethyl acetate in isohexane, togive the desired compound (5.11 g).

¹H NMR δ (CDCl₃): 1.31 (d, 3H), 3.40 (s, 3H), 3.45-3.60 (m, 2H), 3.88(s, 3H), 4.57 (sex, 1H), 5.07 (s, 2H), 6.76 (m, 1H), 7.25 (m, 2H), 7.40(m, 5H). m/z 331 (M+H)⁺.

The preparation of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate wasdescribed earlier.

EXAMPLE 643-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide

A mixture of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide(101 mg, 0.25 mmol), S-(+)-methoxy-2-propanol (0.049 mL, 0.50 mmol) andtriphenyl phosphine (131 mg, 0.50 mmol) in dry THF (10 mL) was treateddropwise with DIAD (0.099 mL, 0.50 mmol) at 0° C. under an argonatmosphere. The mixture was allowed to warm to RT and stirred overnight.The THF was removed by evaporation under reduced pressure and theresidue purified twice by chromatography on silica, eluting with 0-7%methanol in DCM. The desired fractions were combined and purified byelution through an SCX column, eluted with 5% methanol in DCM then 50%7N ammonia (in methanol) in DCM. The desired fractions were purified byelution though an NH₂ column, eluting with 5% methanol in DCM, to givethe desired compound (35 mg) with a purity estimated to be 85%. ¹H NMR δ(CDCl₃): 1.26 (d, 3H), 2.28 (quin, 2H), 2.49 (s, 3H), 3.33 (s, 3H),3.41-3.54 (m, 2H), 4.18 (t, 2H), 4.50-4.58 (m, 1H), 4.64 (t, 2H), 6.77(s, 1H), 7.08 (s, 1H), 7.25 (s, 1H), 7.31 (d, 1H), 8.04 (d, 1H), 8.07(s, 1H), 8.26 (d, 1H), 8.30 (s, 1H), 9.46 (s, 1H); m/z 478 (M+H)⁺

The preparation of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamideis described below.

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(phenylmethyl)oxy]benzamide(3.9 g, 7.9 mmol) was dissolved in ethyl acetate (200 mL) and ethanol(200 mL) then 10% palladium on charcoal added. The reaction was stirredunder an atmosphere of hydrogen for 16 hours. Methanol (150 mL) wasadded to aid solubilisation of the material and the suspension filtered,the residue taken up in DMF, filtered and the combined filtratesevaporated to dryness to give the desired material (3.17 g). ¹H NMR δ(d₆-DMSO): 2.33 (quin, 2H), 2.53 (s, 3H), 4.13 (t, 2H), 4.64 (t, 2H),6.81 (s, 1H), 7.31 (s, 1H), 7.34 (s, 1H), 7.62 (d, 1H), 8.05 (d, 1H),8.40 (s, 1H), 8.47 (s, 1H), 9.26 (s, 1H), 10.35 (s, 1H), 11.02 (s, 1H);m/z 406 (M+H)⁺

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methylpyrazin-2-yl-5-[(phenylmethyl)oxy]benzamide

1-Chloro-N,N,2-trimethyl-1-propenylamine (2.67 mL, 20 mmol) was added toa solution of3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(phenylmethyl)oxy]benzoicacid (6.18 g, 15.3 mmol) in DCM (100 mL) and the reaction stirred at RTfor 50 mins. 2-Amino-5-methylpyrazine (3.34 g, 30.6 mmol) and pyridine(2.5 mL, 30.6 mmol) were added and the reaction stirred overnight. Thesolvent was removed in vacuo, and the residue taken up in ethyl acetate(350 mL). The organic phase was washed with water (2×100 mL), brine (100mL), dried (MgSO₄), filtered, and evaporated in vacuo. The residue waschromatographed on silica, eluting with a gradient of 50-75% ethylacetate in isohexane, to give the desired material (4.01 g). ¹H NMR δ(CDCl₃): 2.28 (quin, 2H), 2.49 (s, 3H), 4.18 (t, 2H), 4.63 (t, 2H), 5.05(s, 2H), 6.78 (s, 1H), 7.10 (s, 1H), 7.25-7.37 (m, 7H), 8.04 (d, 1H),8.07 (s, 1H), 8.25 (s, 2H), 9.46 (s, 1H); m/z 496 (M+H)⁺

3-{[6-(Azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(phenylmethyl)oxy]benzoicacid

A mixture of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (5.16 g, 20mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (5.3 g, 22 mmol),cesium carbonate (19.56 g, 60 mmol) andbromotris(triphenylphosphine)copper (3.73 g, 4 mmol) in DMA (100 mL) wasstirred at 160° C. for 6 hours in a microwave reactor. The DMA wasevaporated under reduced pressure and the residue was dissolved in water(200 mL) and washed with ethyl acetate (3×50 mL). The aqueous layer wasacidified with 2N hydrochloric acid and extracted with ethyl acetate(3×100 mL), the combined organics were washed with water (2×20 mL),brine (20 mL), dried (MgSO₄), filtered and the solvent removed in vacuoto give the desired material (6.18 g). ¹H NMR δ (CDCl₃): 2.29 (s, 2H),4.20 (s, 2H), 4.64 (s, 2H), 5.04 (s, 2H), 6.83 (s, 1H), 7.22-7.44 (m,7H), 7.49 (s, 1H), 7.79-8.63 (m, 2H); m/z 405 (M+H)⁺

The preparations of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate and2-(azetidin-1-ylcarbonyl)-5-bromopyridine were described earlier.

Biological Tests:

The biological effects of the compounds of formula (I) may be tested inthe following way:

(1) Enzymatic Activity

Enzymatic activity of recombinant human pancreatic GLK may be measuredby incubating GLK, ATP and glucose. The rate of product formation may bedetermined by coupling the assay to a G-6-P dehydrogenase, NADP/NADPHsystem and measuring the linear increase with time of optical density at340 nm (Matschinsky et al 1993). Activation of GLK by compounds can beassessed using this assay in the presence or absence of GLKRP asdescribed in Brocklehurst et al (Diabetes 2004, 53, 535-541).

Production of Recombinant GLK and GLKRP:

Human GLK and GLKRP cDNA was obtained by PCR from human pancreatic andhepatic mRNA respectively, using established techniques described inSambrook J, Fritsch EF & Maniatis T, 1989. PCR primers were designedaccording to the GLK and GLKRP cDNA sequences shown in Tanizawa et al1991 and Bonthron, D. T. et al 1994 (later corrected in Warner, J. P.1995).

Cloning in Bluescript II Vectors

GLK and GLKRP cDNA was cloned in E. coli using pBluescript II, (Short etal 1998) a recombinant cloning vector system similar to that employed byYanisch-Perron C et al (1985), comprising a colEI-based replicon bearinga polylinker DNA fragment containing multiple unique restriction sites,flanked by bacteriophage T3 and T7 promoter sequences; a filamentousphage origin of replication and an ampicillin drug resistance markergene.

Transformations

E. Coli transformations were generally carried out by electroporation.400 mL cultures of strains DH5a or BL21(DE3) were grown in L-broth to anOD 600 of 0.5 and harvested by centrifugation at 2,000 g. The cells werewashed twice in ice-cold deionised water, resuspended in 1 mL 10%glycerol and stored in aliquots at −70° C. Ligation mixes were desaltedusing Millipore V Series™ membranes (0.0025 mm) pore size). 40 mL ofcells were incubated with 1 mL of ligation mix or plasmid DNA on ice for10 minutes in 0.2 cm electroporation cuvettes, and then pulsed using aGene Pulser™ apparatus (BioRad) at 0.5 kVcm⁻¹, 250 mF. Transformantswere selected on L-agar supplemented with tetracyline at 10 mg/mL orampicillin at 100 mg/mL.

Expression

GLK was expressed from the vector pTB375NBSE in E. coli BL21 cells,producing a recombinant protein containing a 6-His tag immediatelyadjacent to the N-terminal methionine. Alternatively, another suitablevector is pET21(+)DNA, Novagen, Cat number 697703. The 6-His tag wasused to allow purification of the recombinant protein on a column packedwith nickel-nitrilotriacetic acid agarose purchased from Qiagen (cat no30250).

GLKRP was expressed from the vector pFLAG CTC (IBI Kodak) in E. coliBL21 cells, producing a recombinant protein containing a C-terminal FLAGtag. The protein was purified initially by DEAE Sepharose ion exchangefollowed by utilisation of the FLAG tag for final purification on an M2anti-FLAG immunoaffinity column purchased from Sigma-Aldrich (cat no.A1205).

(2) Oral Glucose Tolerance Test (OGTT)

Oral glucose tolerance tests were done on conscious Zucker obese fa/farats (age 12-13 weeks or older) fed a high fat diet (45% kcal fat) forat least two weeks prior to experimentation. The animals were fasted for2 hours before use for experiments. A test compound or a vehicle wasgiven orally 120 minutes before oral administration of a glucosesolution at a dose of 2 g/kg body weight. Blood glucose levels weremeasured using a Accucheck glucometer from tail bled samples taken atdifferent time points before and after administration of glucose (timecourse of 60 minutes). A time curve of the blood glucose levels wasgenerated and the area-under-the-curve (AUC) for 120 minutes wascalculated (the time of glucose administration being time zero). Percentreduction in glucose excursion was determined using the AUC in thevehicle-control group as zero percent reduction.

Compounds of the invention generally have an activating activity forglucokinase with an EC₅₀ of less than about 1 μM and generally less thanabout 500 nM. For example, Example 3 has an EC₅₀ of 31 nm.

Example 3 exhibits 54% OGTT activity at 10 mg/kg.

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1-16. (canceled) 17: A compound of Formula (I) or a salt thereof,

wherein: R¹ is selected from isopropyl, but-2-yl, cyclopentyl,1,1,1-trifluoroprop-2-yl, 1,3-difluoroprop-2-yl, but-1-yn-3-yl,1-hydroxyprop-2-yl, 2-hydroxybut-3-yl, 1-hydroxybut-2-yl,tetrahydrofuryl, tetrahydropyranyl, 1-methoxyprop-2-yl,1-methoxybut-2-yl, 2-hydroxyprop-1-yl, 2-methoxyprop-1-yl,2-hydroxybut-1-yl, 2-methoxybut-1-yl, 1-fluoromethoxyprop-2-yl,1,1-difluoromethoxyprop-2-yl, and 1-trifluoromethoxyprop-2-yl; HET-1 isa 5- or 6-membered, C-linked heteroaryl ring containing a nitrogen atomin the 2-position and optionally 1 or 2 further ring heteroatomsindependently selected from O, N, and S; which ring is optionallysubstituted on any nitrogen atom by a substituent selected from R⁷and/or on 1 or 2 available carbon atoms by a substituent independentlyselected from R⁶; HET-2 is a 5- or 6-membered heteroaryl ring,containing 1, 2, or 3 ring hetereoatoms independently selected from O,S, and N; which ring is substituted on an available carbon atom by asubstituent selected from R², and is optionally further substituted on 1or 2 available carbon atoms by a substituent independently selected fromR³ and/or on an available nitrogen atom by a substituent selected fromR¹⁰; R² is selected from —C(O)NR⁴R⁵ and —SO₂NR⁴R⁵; R³ is selected frommethyl, trifluoromethyl and halo; R⁴ and R⁵ together with the nitrogenatom to which they are attached form a 4- to 7-membered saturated orpartially unsaturated heterocyclyl ring, optionally containing 1 or 2further heteroatoms (in addition to the linking N atom) independentlyselected from O, N, and S, wherein a —CH₂— group can optionally bereplaced by a —C(O)— and wherein a sulphur atom in the ring mayoptionally be oxidised to a S(O) or S(O)₂ group; which ring isoptionally substituted on an available carbon atom by 1 or 2substituents independently selected from R⁵ and/or on an availablenitrogen atom by a substituent selected from R⁹; or R⁴ and R⁵ togetherwith the nitrogen atom to which they are attached form a 6- to10-membered bicyclic saturated or partially unsaturated heterocyclylring, optionally containing 1 further nitrogen atom, wherein a —CH₂—group can optionally be replaced by a —C(O)—; which ring is optionallysubstituted on an available carbon by 1 substituent selected fromhydroxy and R³ or on an available nitrogen atom by methyl; R⁶ isindependently selected from (1-4C)alkyl, halo, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,(1-4C)alkylamino(1-4C)alkyl, and di(1-4C)alkylamino(1-4C)alkyl; R⁷ isindependently selected from (1-4C)alkyl, halo(1-4C)alkyl,dihalo(1-4C)alkyl, trihalo(1-4C)alkyl, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylS(O)p(1-4C)alkyl, amino(1-4C)alkyl,(1-4C)alkylamino(1-4C)alkyl, and di(1-4C)alkylamino(1-4C)alkyl; R⁸ isselected from hydroxy, (1-4C)alkoxy, (1-4C)alkyl, aminocarbonyl,(1-4C)alkylaminocarbonyl, di(1-4C)alkylaminocarbonyl, (1-4C)alkylamino,di(1-4C)alkylamino, (1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and—S(O)p(1-4C)alkyl; R⁹ is selected from (1-4C)alkyl, —C(O)(1-4C)alkyl,aminocarbonyl, (1-4C)alkylaminocarbonyl, di(1-4C)alkylaminocarbonyl,(1-4C)alkoxy(1-4C)alkyl, hydroxy(1-4C)alkyl, and —S(O)p(1-4C)alkyl; R¹⁰is selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, —C(O)(1-4C)alkyl, benzyl, and(1-4C)alkylsulfonyl; p is independently 0, 1, or 2; provided that thecompound is not3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3-ylbenzamide;or3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide18: A compound of Formula (I) as claimed in claim 17 or a salt thereof,wherein R¹ is of sub-formula X:

wherein R^(x) is selected from methyl, ethyl, trifluoromethyl, ethynyl,hydroxymethyl, hydroxyethyl, methoxymethyl, fluoromethoxymethyl,difluoromethoxymethyl, and trifluoromethoxymethyl. 19: A compound ofFormula (I) as claimed in claim 17 or claim 18, or a salt thereof,wherein R² is —CONR⁴R⁵. 20: A compound of the Formula (I) as claimed inclaim 17 or a salt thereof, wherein, R¹ is selected from isopropyl,cyclopentyl, 1,3-difluoroprop-2-yl, but-2-yl, 1-hydroxyprop-2-yl,2-hydroxybut-3-yl, 1,1-difluoromethoxyprop-2-yl, tetrahydrofuryl,tetrahydropyranyl, 1-hydroxybut-2-yl, and 1-methoxyprop-2-yl; HET-1 isselected from thiazolyl, pyrazolyl, thiadiazolyl, pyridyl, isoxazolyl,and pyrazinyl, wherein R¹ is optionally substituted with a methyl,isopropyl, or ethyl group, and/or by fluoro; HET-2 is selected frompyridyl, pyrazinyl, pyridazinyl, thiazolyl, and pyrimidinyl, substitutedwith R² and optionally substituted with R³; R³ is methyl, fluoro, orchloro; R² is selected from —C(O)NR⁴R⁵ and —SO—NR⁴R⁵; R⁴ and R⁵ togetherform an azetidinyl, 7-azabicyclo[2.2.1]hept-7-yl, morpholino, orpyrrolidinyl ring. 21: A compound of Formula (I) as claimed in claim 17or a salt thereof, wherein, R¹ is selected from isopropyl, cyclopentyl,1,3-difluoroprop-2-yl, but-2-yl, 1-hydroxyprop-2-yl, 2-hydroxybut-3-yl,1,1-difluoromethoxyprop-2-yl, tetrahydrofuryl, tetrahydropyranyl,1-hydroxybut-2-yl, and 1-methoxyprop-2-yl; HET-1 is selected fromthiazolyl, pyrazolyl, thiadiazolyl, pyridyl, isoxazolyl, and pyrazinyl,wherein R¹ is optionally substituted with a methyl, isopropyl, or ethylgroup, and/or by fluoro; HET-2 is selected from pyridyl, pyrazinyl,pyridazinyl, thiazolyl, and pyrimidinyl, substituted with R² andoptionally substituted with R³; R³ is methyl, fluoro or chloro; R² is—CONR⁴R⁵; R⁴ and R⁵ together form an azetidinyl or pyrrolidinyl ring.22: A compound of Formula (I) as claimed in claim 17, or a salt thereof,wherein R⁴ and R⁵ together form an azetidinyl ring. 23: A compound ofFormula (I) as claimed in claim 17 which is a compound of Formula (IA)or a salt thereof:

wherein each of X¹, X², and X³ is independently selected from CH, N, S,and O; X⁴ is absent, or is selected from CH, N, O, and S; provided thatat least one of X¹, X², X³, and X⁴ is CH and provided that there are noO—O, O—S, or S—S bonds within the ring. 24: A compound of the Formula(I) as claimed in claim 17, which is any one or more of the following:3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{L[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-1,3-thiazol-2-ylbenzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;3-{[5-(azetidin-1-ylsulfonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[3-chloro-5-(morpholin-4-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;and3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;and/or3-{[5-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[2-(azetidin-1-ylcarbonyl)pyrimidin-5-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[2-(azetidin-1-ylcarbonyl)pyrimidin-5-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[4-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[4-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide;and3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-(hydroxymethyl)propyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;and/or3-{[2-(azetidin-1-ylcarbonyl)pyrimidin-5-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-(cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-(cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-(cyclopentyloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[4-(azetidin-1-ylcarbonyl)-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1,3-thiazol-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyridin-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1-methylethyl)oxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1-methylethyl)oxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(1-methylethyl)oxy]benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyridin-2-ylbenzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-isoxazol-3-yl-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3-ylbenzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-1H-pyrazol-3-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1,5-dimethyl-1H-pyrazol-3′-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridazin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(4-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-1H-pyrazol-3-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(4-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-ethyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-1H-pyrazol-3-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-fluoropyridin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[3-chloro-5-(pyrrolidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide;3-{[3-chloro-5-(pyrrolidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[3-chloro-5-(pyrrolidin-1-ylcarbonyl)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methylpyrazin-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide;and/or3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-isoxazol-3-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-pyrazin-2-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-(5-fluoropyridin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyridin-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-isoxazol-3-yl-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(4-methyl-1,3-thiazol-2-yl)benzamide;3-[{5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methyl-1,3-thiazol-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyrazin-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-pyrazin-2-ylbenzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyrazin-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[(1-methylethyl)oxy]-N-pyrazin-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-pyrazin-2-ylbenzamide;3-{[3-chloro-5-(morpholin-4-ylcarbonyl)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;and3-{[5-(azetidin-1-ylcarbonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;and/or3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-pyrazin-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-pyridin-2-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)pyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzamide;N-(1-methyl-1H-pyrazol-3-yl)-3-{[6-(pyrrolidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-pyrazin-2-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-(5-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-1H-pyrazol-3-yl-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(5-methyl-1H-pyrazol-3-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-1H-pyrazol-3-ylbenzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-N-1H-pyrazol-3-ylbenzamide;3-{[5-(azetidin-1-ylsulfonyl)-4-methyl-1,3-thiazol-2-yl]oxy}-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide;3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide;and/or3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide;or a salt thereof. 25: A pharmaceutical composition comprising acompound as claimed in claim 17, or a pharmaceutically-acceptable saltthereof, together with a pharmaceutically acceptable diluent or carrier.26: A method of treating GLK mediated diseases comprising administeringan effective amount of a compound of Formula (I) as claimed in claim 17or a compound of Formula (IA) as claimed in claim 23 or apharmaceutically-acceptable salt thereof, to a mammal in need of suchtreatment. 27: The method of claim 26, wherein the GLK mediated diseaseis type 2 diabetes. 28: A process for the preparation of a compound ofFormula (I) as claimed in claim 17 or a compound of Formula (IA) asclaimed in claim 18, comprising: (a) reacting an acid of Formula (III)or activated derivative thereof with a compound of Formula (IV), whereinR¹ is as defined for Formula (I) or Formula (IA) defined or a protectedversion thereof;

or (b) reacting a compound of Formula (V) with a compound of Formula(VI),

wherein X¹ is a leaving group and X² is a hydroxyl group, or X¹ is ahydroxyl group and X² is a leaving group; and wherein R¹ is as definedfor Formula (I) or Formula (IA) or a protected version thereof; orreacting a compound of Formula (V) with the intermediate ester ofFormula (VII), wherein P¹ is a protecting group as hereinafterdescribed, followed by ester hydrolysis and amide formation;

or (c) reacting a compound of Formula (VIII) with a compound of Formula(IX)

wherein X³ is a leaving group or an organometallic reagent and X⁴ is ahydroxyl group; or X³ is a hydroxyl group and X⁴ is a leaving group oran organometallic reagent, and wherein R¹ is as hereinbefore defined ora protected version thereof; or reacting a compound of Formula (VIII)with the intermediate ester of Formula (X), followed by ester hydrolysisand amide formation;

or (d) reacting a compound of Formula (XI) with a compound of Formula(XII),

wherein X⁵ is a leaving group; and wherein R¹ is as hereinbefore definedor a protected version thereof; or e) reacting R^(2a) on a compound ofFormula (XIII) with an amine of Formula NR⁴R⁵

wherein R^(2a) is a precursor to R²; and thereafter, if necessary: i)converting a compound of Formula (I) into another compound of Formula(I); ii) removing any protecting groups; and/or iii) forming a saltthereof. 29: The method of claim 28, wherein in process (e), when R² is—CONR⁴R⁵ then R² is a carboxylic acid, ester or anhydride and when R² is—SO²NR⁴R⁵ then R^(2a) is a sulfonic acid equivalent.